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Graber M, Gollmann-Tepeköylü C, Schweiger V, Hirsch J, Pölzl L, Nägele F, Lener D, Hackl H, Sopper S, Kirchmair E, Mair S, Voelkl J, Plattner C, Eichin F, Trajanoski Z, Krogsdam A, Eder J, Fiegl M, Hau D, Tancevski I, Grimm M, Cooke JP, Holfeld J. Modulation of cell fate by shock wave therapy in ischaemic heart disease. EUROPEAN HEART JOURNAL OPEN 2025; 5:oeaf011. [PMID: 40201592 PMCID: PMC11977462 DOI: 10.1093/ehjopen/oeaf011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 12/10/2024] [Accepted: 02/06/2025] [Indexed: 04/10/2025]
Abstract
Aims Cardiac shockwave therapy (SWT) improves left ventricular (LV) function in patients with ischaemic cardiomyopathy. Shockwave therapy activates Toll-like receptor 3 (TLR3), a receptor-inducing chromatin remodelling and nuclear reprogramming of cardiac cells. We hypothesized that mechanical activation of TLR3 facilitates reprogramming of fibroblasts towards endothelial cells restoring myocardial perfusion and function. Methods and results Human cardiac fibroblasts were treated by mechanical stimulation via SWT or TLR3 agonist Poly(I:C) in the presence of endothelial induction medium. A lineage tracing experiment was performed in a transgenic mouse model of Fsp1-Cre/LacZ mice after coronary occlusion. Left ventricular function and scarring were assessed. Single-cell sequencing including RNA trajectory analysis was performed. Chromatin remodelling and epigenetic plasticity were evaluated via western blot and Assay for Transposase-Accessible Chromatin sequencing. Mechanical stimulation of human fibroblasts with SWT activated TLR3 signalling and enhanced the expression of endothelial genes in a TLR3-dependent fashion. The induced endothelial cells (ECs) resembled genuine ECs in that they produced endothelial nitric oxide and formed tube-like structures in Matrigel. In a lineage tracing experiment in Fsp1-Cre/LacZ mice, shockwave treatment increased LacZ/CD31-positive cells (indicating transdifferentiation) after coronary occlusion. Furthermore, SWT reduced myocardial scar size and improved LV function. Single-cell RNA-seq and RNA trajectory analyses revealed that SWT induced an endothelial fibroblast cluster and mechanical stimulation induced significant changes in chromatin organization, with chromatin being more accessible after both treatments in 1705 genomic regions. Conclusion Shockwave therapy enhances DNA accessibility via TLR3 activation and facilitates the transdifferentiation of fibroblasts towards endothelial cells in ischaemic myocardium.
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Affiliation(s)
- Michael Graber
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
- Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Can Gollmann-Tepeköylü
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| | - Victor Schweiger
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| | - Jakob Hirsch
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| | - Leo Pölzl
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
- Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Felix Nägele
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| | - Daniela Lener
- Department of Internal Medicine, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Hubert Hackl
- Institute of Bioinformatics, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Sieghart Sopper
- Department of Hematology and Oncology, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Elke Kirchmair
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| | - Sophia Mair
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| | - Jakob Voelkl
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria
| | - Christina Plattner
- Institute of Bioinformatics, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Felix Eichin
- Institute of Bioinformatics, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Zlatko Trajanoski
- Institute of Bioinformatics, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Anne Krogsdam
- Institute of Bioinformatics, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Jonas Eder
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| | - Manuel Fiegl
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| | - Dominik Hau
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| | - Ivan Tancevski
- Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Michael Grimm
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| | - John P Cooke
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., Mail Stop: R10-South, Houston, TX 77030, USA
| | - Johannes Holfeld
- Department of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
- Department of Cardiovascular Surgery, German Heart Center Munich, School of Medicine and Health, Technical University of Munich, Lazarettstraße 36, 80636 Munich, Germany
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Huangfu Q, Zhang J, Xu J, Xu J, Yang Z, Wei J, Yang L, Shu Y, Sun C, Wang B, Chen Y, Wen J, Cai M. Mechanosensitive Ca 2+ channel TRPV1 activated by low-intensity pulsed ultrasound ameliorates acute kidney injury through Notch1-Akt-eNOS signaling. FASEB J 2025; 39:e70304. [PMID: 39785696 DOI: 10.1096/fj.202401142rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 12/15/2024] [Accepted: 12/26/2024] [Indexed: 01/12/2025]
Abstract
Acute Kidney Injury (AKI) is a significant medical condition characterized by the abrupt decline in kidney function.Low-intensity pulsed ultrasound (LIPUS), a non-invasive therapeutic technique employing low-intensity acoustic wave pulses, has shown promise in promoting tissue repair and regeneration. A novel LIPUS system was developed and evaluated in rat AKI models, focusing on its effects on glomerular filtration rate (GFR), blood urea nitrogen (BUN), serum creatinine (SCr), and the Notch1-Akt-eNOS signaling pathway. The results demonstrated that LIPUS treatment improved GFR, BUN, SCr levels, and renal pathology in AKI rats. In vitro experiments using HUVEC cells revealed that LIPUS stimulation promoted angiogenesis, cell migration mechanically-dependent calcium ion influx, which was partially attenuated by TRPV1 knockdown. RNA sequencing analysis indicated LIPUS-induced activation of the Notch pathway, phosphorylation of Akt and eNOS. Furthermore, inhibition or genetic silencing of Notch1 abolished the beneficial effects of LIPUS on angiogenesis, renal function, and Akt-eNOS phosphorylation in both cells and AKI rats. These findings suggest that LIPUS-induced calcium influx promotes Akt-eNOS phosphorylation, nitric oxide (NO) production, angiogenesis, and improved renal function in AKI via Notch1-Akt-eNOS signaling, positioning LIPUS as a promising therapeutic strategy for AKI by targeting vascular regeneration.
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Affiliation(s)
- Qi Huangfu
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jun Zhang
- Hangzhou Applied Acoustics Research Institute, Hangzhou, China
| | - Jiaju Xu
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jinming Xu
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhangcheng Yang
- Hangzhou Applied Acoustics Research Institute, Hangzhou, China
| | - Jingchao Wei
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Liuqing Yang
- Hangzhou Applied Acoustics Research Institute, Hangzhou, China
| | - Yichang Shu
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chengfang Sun
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bohan Wang
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi Chen
- Hangzhou Applied Acoustics Research Institute, Hangzhou, China
| | - Jiaming Wen
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ming Cai
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Goldstein SW, Kim NN, Goldstein I. Randomized trial of low intensity shockwave therapy for erectile dysfunction utilizing grayscale ultrasound for analysis of erectile tissue homogeneity/inhomogeneity. Transl Androl Urol 2024; 13:2246-2267. [PMID: 39507857 PMCID: PMC11535730 DOI: 10.21037/tau-24-338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 10/11/2024] [Indexed: 11/08/2024] Open
Abstract
Background Electrohydraulic shockwave devices have been Food and Drug Administration-cleared for improved blood flow and connective tissue activation and have been used to treat erectile dysfunction (ED). In this study, the main focus was to evaluate improvement in erectile tissue quality after low intensity shockwave therapy (LiSWT). Methods A single-blind, sham-controlled, randomized, prospective study, was performed in men with ED naïve to shockwave or radial ballistic pressure wave therapy. Participants were randomized 1:2 to simulated (sham) or active LiSWT treatment. After simulated treatments, participants in the Sham Arm were converted to active LiSWT, while participants initially in the Active Treatment Arm received no further treatment. Assessments were performed at baseline and two follow-up visits. Subjective parameters of erectile function (EF) were assessed by total and EF domain scores of the International Index of Erectile Function (IIEF) and sexual encounter profile (SEP). Objective parameters of penile erection were measurements of hypoechoic areas in images obtained by grayscale ultrasound (GUS) with high resolution 15.4 MHz probe and cavernosal artery peak systolic velocity (PSV) and end diastolic velocity (EDV) by color duplex Doppler ultrasound (DUS). Outcome measures for erectile and urinary function were also obtained. Results Simulated LiSWT did not significantly change any assessment parameter. Sham Arm participants who converted to active LiSWT had significantly increased mean IIEF total (P=0.02) and IIEF-EF scores that approached statistical significance (P=0.06), relative to baseline. Similarly, at the end of the study, Active Treatment Arm participants had significantly increased mean IIEF total (P=0.02) and IIEF-EF scores that approached statistical significance (P=0.07), relative to baseline. Additionally, at the end of the study, SEP3 success rates (erection lasting long enough for successful intercourse) approached statistical significance when Sham Arm participants were converted to active LiSWT (P=0.08) and reached statistical significance in the Active Treatment Arm (P=0.049). GUS assessments by visual grading were significantly correlated to IIEF-EF score (P=0.002) and were significantly increased relative to baseline in the Active Treatment Arm at follow-up Assessment 1 (P=0.03) and Assessment 2 (P=0.04). The greatest reduction in hypoechoic area after LiSWT occurred in the proximal penile shaft. EDV was also significantly reduced in the Active Treatment Arm at follow-up Assessment 1 (P=0.04) and Assessment 2 (P=0.04). LiSWT also resulted in improved prostate symptom scores, approaching significance in the Active Treatment Arm (P=0.055) with no changes in prostate-specific antigen. Treatment-related adverse events were limited and transient. Conclusions In this prospective trial, LiSWT was safe and efficacious for erectile symptoms using GUS imaging as a novel, non-invasive method to assess improvements in corporal veno-occlusive function. Improved veno-occlusion and reduced hypoechoic area demonstrated by GUS imaging suggest that LiSWT decreases connective tissue content in penile erectile tissue. Lower urinary tract symptoms also improved with LiSWT. Trial Registration NCT06600893 on clinicaltrials.gov.
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Affiliation(s)
| | - Noel N. Kim
- Institute for Sexual Medicine, San Diego, CA, USA
| | - Irwin Goldstein
- San Diego Sexual Medicine, San Diego, CA, USA
- Sexual Medicine, University of California San Diego Health East Campus, San Diego, CA, USA
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Holfeld J, Nägele F, Pölzl L, Engler C, Graber M, Hirsch J, Schmidt S, Mayr A, Troger F, Pamminger M, Theurl M, Schreinlechner M, Sappler N, Ruttmann-Ulmer E, Schaden W, Cooke JP, Ulmer H, Bauer A, Gollmann-Tepeköylü C, Grimm M. Cardiac shockwave therapy in addition to coronary bypass surgery improves myocardial function in ischaemic heart failure: the CAST-HF trial. Eur Heart J 2024; 45:2634-2643. [PMID: 38898573 DOI: 10.1093/eurheartj/ehae341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 05/02/2024] [Accepted: 05/16/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND AND AIMS In chronic ischaemic heart failure, revascularisation strategies control symptoms but are less effective in improving left ventricular ejection fraction (LVEF). The aim of this trial is to investigate the safety of cardiac shockwave therapy (SWT) as a novel treatment option and its efficacy in increasing cardiac function by inducing angiogenesis and regeneration in hibernating myocardium. METHODS In this single-blind, parallel-group, sham-controlled trial (cardiac shockwave therapy for ischemic heart failure, CAST-HF; NCT03859466) patients with LVEF ≤40% requiring surgical revascularisation were enrolled. Patients were randomly assigned to undergo direct cardiac SWT or sham treatment in addition to coronary bypass surgery. The primary efficacy endpoint was the improvement in LVEF measured by cardiac magnetic resonance imaging from baseline to 360 days. RESULTS Overall, 63 patients were randomized, out of which 30 patients of the SWT group and 28 patients of the Sham group attained 1-year follow-up of the primary endpoint. Greater improvement in LVEF was observed in the SWT group (Δ from baseline to 360 days: SWT 11.3%, SD 8.8; Sham 6.3%, SD 7.4, P = .0146). Secondary endpoints included the 6-minute walking test, where patients randomized in the SWT group showed a greater Δ from baseline to 360 days (127.5 m, SD 110.6) than patients in the Sham group (43.6 m, SD 172.1) (P = .028) and Minnesota Living with Heart Failure Questionnaire score on day 360, which was 11.0 points (SD 19.1) for the SWT group and 17.3 points (SD 15.1) for the Sham group (P = .15). Two patients in the treatment group died for non-device-related reasons. CONCLUSIONS In conclusion, the CAST-HF trial indicates that direct cardiac SWT, in addition to coronary bypass surgery improves LVEF and physical capacity in patients with ischaemic heart failure.
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Affiliation(s)
- Johannes Holfeld
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Felix Nägele
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
- Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA
| | - Leo Pölzl
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Clemens Engler
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Michael Graber
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
- Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA
| | - Jakob Hirsch
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Sophia Schmidt
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Agnes Mayr
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Troger
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Mathias Pamminger
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Theurl
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael Schreinlechner
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Nikolay Sappler
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Elfriede Ruttmann-Ulmer
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Wolfgang Schaden
- The Research Center in Cooperation with AUVA, Ludwig Boltzmann Institute for Traumatology, Vienna, Austria
- International Medical Director of SoftWave Tissue Regeneration Technologies, Kennesaw, GA, USA
| | - John P Cooke
- Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA
| | - Hanno Ulmer
- Institute of Medical Statistics and Informatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Axel Bauer
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Can Gollmann-Tepeköylü
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Michael Grimm
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
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Liu T, Shi J, Fu Y, Zhang Y, Bai Y, He S, Deng W, Jin Q, Chen Y, Fang L, He L, Li Y, Yang Y, Zhang L, Lv Q, Wang J, Xie M. New trends in non-pharmacological approaches for cardiovascular disease: Therapeutic ultrasound. Trends Cardiovasc Med 2023; 33:431-440. [PMID: 35461990 DOI: 10.1016/j.tcm.2022.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 04/05/2022] [Accepted: 04/19/2022] [Indexed: 11/30/2022]
Abstract
Significant advances in application of therapeutic ultrasound have been reported in the past decades. Therapeutic ultrasound is an emerging non-invasive stimulation technique. This approach has shown high potential for treatment of various disease including cardiovascular disease. In this review, application principle and significance of the basic parameters of therapeutic ultrasound are summarized. The effects of therapeutic ultrasound in myocardial ischemia, heart failure, myocarditis, arrhythmias, and hypertension are explored, with key focus on the underlying mechanism. Further, the limitations and challenges of ultrasound therapy on clinical translation are evaluated to promote application of the novel strategy in cardiovascular diseases.
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Affiliation(s)
- Tianshu Liu
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Jiawei Shi
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Yanan Fu
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Yichan Zhang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Ying Bai
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Shukun He
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Wenhui Deng
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Qiaofeng Jin
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Yihan Chen
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Lingyun Fang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Lin He
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Yuman Li
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Yali Yang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Li Zhang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Qing Lv
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Jing Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China.
| | - Mingxing Xie
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Medical Imaging, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China.
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Imtiaz C, Farooqi MA, Bhatti T, Lee J, Moin R, Kang CU, Farooqi HMU. Focused Ultrasound, an Emerging Tool for Atherosclerosis Treatment: A Comprehensive Review. Life (Basel) 2023; 13:1783. [PMID: 37629640 PMCID: PMC10455721 DOI: 10.3390/life13081783] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/08/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
Focused ultrasound (FUS) has emerged as a promising noninvasive therapeutic modality for treating atherosclerotic arterial disease. High-intensity focused ultrasound (HIFU), a noninvasive and precise modality that generates high temperatures at specific target sites within tissues, has shown promising results in reducing plaque burden and improving vascular function. While low-intensity focused ultrasound (LIFU) operates at lower energy levels, promoting mild hyperthermia and stimulating tissue repair processes. This review article provides an overview of the current state of HIFU and LIFU in treating atherosclerosis. It focuses primarily on the therapeutic potential of HIFU due to its higher penetration and ability to achieve atheroma disruption. The review summarizes findings from animal models and human trials, covering the effects of FUS on arterial plaque and arterial wall thrombolysis in carotid, coronary and peripheral arteries. This review also highlights the potential benefits of focused ultrasound, including its noninvasiveness, precise targeting, and real-time monitoring capabilities, making it an attractive approach for the treatment of atherosclerosis and emphasizes the need for further investigations to optimize FUS parameters and advance its clinical application in managing atherosclerotic arterial disease.
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Affiliation(s)
- Cynthia Imtiaz
- Ocean and Biomedical Ultrasound Laboratory, Department of Ocean System Engineering, Jeju National University, Jeju-si 63243, Republic of Korea; (C.I.)
| | - Muhammad Awais Farooqi
- Department of Mechatronics Engineering, Jeju National University, Jeju-si 63243, Republic of Korea
| | - Theophilus Bhatti
- Interdisciplinary Department of Advanced Convergence Technology and Science, College of Pharmacy, Jeju National University, Jeju 63243, Republic of Korea
| | - Jooho Lee
- Ocean and Biomedical Ultrasound Laboratory, Department of Ocean System Engineering, Jeju National University, Jeju-si 63243, Republic of Korea; (C.I.)
| | - Ramsha Moin
- Department of Pediatrics, Elaj Hospital, Gujranwala 52250, Pakistan
| | - Chul Ung Kang
- Department of Mechatronics Engineering, Jeju National University, Jeju-si 63243, Republic of Korea
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7
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Gollmann-Tepeköylü C, Graber M, Hirsch J, Mair S, Naschberger A, Pölzl L, Nägele F, Kirchmair E, Degenhart G, Demetz E, Hilbe R, Chen HY, Engert JC, Böhm A, Franz N, Lobenwein D, Lener D, Fuchs C, Weihs A, Töchterle S, Vogel GF, Schweiger V, Eder J, Pietschmann P, Seifert M, Kronenberg F, Coassin S, Blumer M, Hackl H, Meyer D, Feuchtner G, Kirchmair R, Troppmair J, Krane M, Weiss G, Tsimikas S, Thanassoulis G, Grimm M, Rupp B, Huber LA, Zhang SY, Casanova JL, Tancevski I, Holfeld J. Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification. Circulation 2023; 147:1518-1533. [PMID: 37013819 PMCID: PMC10192061 DOI: 10.1161/circulationaha.122.063481] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 03/08/2023] [Indexed: 04/05/2023]
Abstract
BACKGROUND Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. METHODS Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3, and IFN-α/β receptor alpha chain (Ifnar1)-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. RESULTS Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn-/-, Tlr3-/-, and Ifnar1-/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/β receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. CONCLUSIONS This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.
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Affiliation(s)
| | - Michael Graber
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Jakob Hirsch
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Sophia Mair
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Andreas Naschberger
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
- Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia
| | - Leo Pölzl
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Nägele
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Elke Kirchmair
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Gerald Degenhart
- Department of Radiology, Core Facility for Micro-CT, Medical University of Innsbruck, Innsbruck, Austria
| | - Egon Demetz
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Richard Hilbe
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Hao-Yu Chen
- Preventive and Genomic Cardiology, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - James C. Engert
- Preventive and Genomic Cardiology, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Anna Böhm
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Nadja Franz
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Daniela Lobenwein
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Daniela Lener
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Christiane Fuchs
- Department Life Science Engineering, University of Applied Sciences Technikum Wien, Vienna, Austria
| | - Anna Weihs
- Department Life Science Engineering, University of Applied Sciences Technikum Wien, Vienna, Austria
| | - Sonja Töchterle
- Institute of Molecular Biology/CMBI, University of Innsbruck, Innsbruck, Austria
| | - Georg F. Vogel
- Department of Pediatrics/Institute of Cell biology, Medical University of Innsbruck, Innsbruck, Austria
| | - Victor Schweiger
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Jonas Eder
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Peter Pietschmann
- Division of Cellular and Molecular Pathophysiology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Markus Seifert
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Florian Kronenberg
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Coassin
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael Blumer
- Institute of Clinical and Functional Anatomy, Innsbruck Medical University, Innsbruck, Austria
| | - Hubert Hackl
- Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Dirk Meyer
- Institute of Molecular Biology/CMBI, University of Innsbruck, Innsbruck, Austria
| | - Gudrun Feuchtner
- Department of Radiology, Core Facility for Micro-CT, Medical University of Innsbruck, Innsbruck, Austria
| | - Rudolf Kirchmair
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Jakob Troppmair
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, University of Innsbruck, Innsbruck, Innsbruck, Austria
| | - Markus Krane
- Department of Cardiovascular Surgery, German Heart Center Munich at the Technical University Munich, Munich, Germany
| | - Günther Weiss
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Sotirios Tsimikas
- Division of Cardiovascular Diseases, University of California, San Diego, La Jolla, USA
| | - George Thanassoulis
- Preventive and Genomic Cardiology, McGill University Health Centre Research Institute, Montreal, QC, Canada
| | - Michael Grimm
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Bernhard Rupp
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Lukas A. Huber
- Institute of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria
- Austrian Drug Screening Institute, ADSI, Innsbruck, Austria
| | - Shen-Ying Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
- Howard Hughes Medical Institute, New York, NY, USA
| | - Ivan Tancevski
- Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Johannes Holfeld
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
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Skov-Jeppesen SM, Petersen NA, Yderstraede KB, Jensen BL, Bistrup C, Lund L. Low-Intensity Extracorporeal Shockwave Therapy (LI-ESWT) in Renal Diseases: A Review of Animal and Human Studies. Int J Nephrol Renovasc Dis 2023; 16:31-42. [PMID: 36778197 PMCID: PMC9912820 DOI: 10.2147/ijnrd.s389219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 01/25/2023] [Indexed: 02/09/2023] Open
Abstract
Background Low-intensity extracorporeal shockwave therapy (LI-ESWT) has been suggested as a treatment for vascular diseases such as ischemic heart disease, diabetic foot ulcers, and erectile dysfunction. Primarily, LI-ESWT is known for its ability to stimulate angiogenesis and activation of stem cells in target tissues. Application of LI-ESWT in chronic progressive renal diseases is a novel area. The aim of the present review was to summarize available data on the effects of LI-ESWT used in the setting of renal diseases. Methods We systematically searched PubMed, Medline, and Embase databases for relevant studies. Our review included the results from preclinical animal experiments and clinical research. Results Eleven animal studies and one clinical study were included in the review. In the animal studies, LI-ESWT was used for the treatment of hypertensive nephropathy (n=1), diabetic nephropathy (n=1), or various types of ischemic renal injury (ie, artery occlusion, reperfusion injury) (n=9). The clinical study was conducted in a single-arm cohort as a Phase 1 study with patients having diabetic nephropathy. In animal studies, the application of LI-ESWT was associated with several effects: LI-ESWT led to increased VEGF and endothelial cell proliferation and improved vascularity and perfusion of the kidney tissue. LI-ESWT reduced renal inflammation and fibrosis. LI-ESWT caused only mild side effects in the clinical study, and, similarly, there were no signs of kidney injury after LI-ESWT in the animal studies. Conclusion LI-ESWT, as a non-invasive treatment, reduces the pathological manifestations (inflammation, capillary rarefaction, fibrosis, decreased perfusion) associated with certain types of renal disease. The efficacy of renal LI-ESWT needs to be confirmed in randomized clinical trials.
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Affiliation(s)
- Sune Moeller Skov-Jeppesen
- Department of Urology, Odense University Hospital, Odense, Denmark,Clinical Institute, University of Southern Denmark, Odense, Denmark,Correspondence: Sune Moeller Skov-Jeppesen, Department of Urology, Odense University Hospital, Sdr. Boulevard 29, Odense, 5000, Denmark, Tel +45 51210911, Fax +45 65411726, Email
| | | | - Knud Bonnet Yderstraede
- Clinical Institute, University of Southern Denmark, Odense, Denmark,Department of Endocrinology, Odense University Hospital, Odense, Denmark
| | - Boye L Jensen
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Claus Bistrup
- Clinical Institute, University of Southern Denmark, Odense, Denmark,Department of Nephrology, Odense University Hospital, Odense, Denmark
| | - Lars Lund
- Department of Urology, Odense University Hospital, Odense, Denmark,Clinical Institute, University of Southern Denmark, Odense, Denmark
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9
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Mason MM, Pai RK, Masterson JM, Lokeshwar SD, Chu KY, Ramasamy R. Low-intensity extracorporeal shockwave therapy for diabetic men with erectile dysfunction: A systematic scoping review. Andrology 2023; 11:270-281. [PMID: 35642619 DOI: 10.1111/andr.13197] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/08/2022] [Accepted: 05/26/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND Erectile dysfunction (ED) is a very common complication in men with diabetes mellitus (DM). Low-intensity extracorporeal shockwave therapy (Li-ESWT) offers a promising nonsurgical treatment option for ED. A systematic scoping review investigating the outcomes of Li-ESWT in diabetic men with ED has not yet been performed. OBJECTIVES To systematically review animal and clinical studies related to the use of Li-ESWT for treatment of DM-related ED. DATA SOURCES PubMed, Embase, The Cochrane Library, Scopus, and Web of Science were searched, unrestricted by dates or study design. MATERIALS AND METHODS We included qualitative studies, quantitative studies, primary research studies, meta-analyses, and research letters written in English. Full text reviewing was completed in all animal and human studies discussing Li-ESWT for the treatment of ED in subjects with DM. Data extracted included the journal citation, publication year, country of origin, study design, and a summary of the pertinent findings. RESULTS Our search yielded nine clinical studies and 10 animal studies. The results of the clinical studies suggest that Li-ESWT is a safe and effective treatment in men with well-controlled DM and moderate or better ED. However, the benefit is less durable in diabetic men than nondiabetic men. The results of the animal studies suggest that Li-ESWT can significantly improve erectile function in diabetic rat models with ED. CONCLUSIONS The examined studies present encouraging results for the use of Li-ESWT to treat diabetic men with ED. Future studies, particularly robust randomized controlled trials, are necessary to confirm these findings and provide long-term follow-up.
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Affiliation(s)
- Matthew M Mason
- University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Raghav K Pai
- University of Miami Miller School of Medicine, Miami, Florida, USA
| | - John M Masterson
- Department of Surgery, Division of Urology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Soum D Lokeshwar
- Department of Urology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Kevin Y Chu
- University of Miami Miller School of Medicine, Miami, Florida, USA
- Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Ranjith Ramasamy
- University of Miami Miller School of Medicine, Miami, Florida, USA
- Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
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10
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Tassinari R, Olivi E, Cavallini C, Taglioli V, Zannini C, Marcuzzi M, Fedchenko O, Ventura C. Mechanobiology: A landscape for reinterpreting stem cell heterogeneity and regenerative potential in diseased tissues. iScience 2023; 26:105875. [PMID: 36647385 PMCID: PMC9839966 DOI: 10.1016/j.isci.2022.105875] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Mechanical forces play a fundamental role in cellular dynamics from the molecular level to the establishment of complex heterogeneity in somatic and stem cells. Here, we highlight the role of cytoskeletal mechanics and extracellular matrix in generating mechanical forces merging into oscillatory synchronized patterns. We discuss how cellular mechanosensing/-transduction can be modulated by mechanical forces to control tissue metabolism and set the basis for nonpharmacologic tissue rescue. Control of bone anabolic activity and repair, as well as obesity prevention, through a fine-tuning of the stem cell morphodynamics are highlighted. We also discuss the use of mechanical forces in the treatment of cardiovascular diseases and heart failure through the fine modulation of stem cell metabolic activity and regenerative potential. We finally focus on the new landscape of delivering specific mechanical stimuli to reprogram tissue-resident stem cells and enhance our self-healing potential, without the need for stem cell or tissue transplantation.
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Affiliation(s)
| | - Elena Olivi
- ELDOR LAB, via Corticella 183, 40129 Bologna, Italy
| | | | | | | | - Martina Marcuzzi
- NIBB, National Institute of Biostructures and Biosystems, National Laboratory of Molecular Biology and Stem Cell Engineering, via Corticella 183, 40129 Bologna, Italy
| | - Oleksandra Fedchenko
- NIBB, National Institute of Biostructures and Biosystems, National Laboratory of Molecular Biology and Stem Cell Engineering, via Corticella 183, 40129 Bologna, Italy
| | - Carlo Ventura
- ELDOR LAB, via Corticella 183, 40129 Bologna, Italy
- NIBB, National Institute of Biostructures and Biosystems, National Laboratory of Molecular Biology and Stem Cell Engineering, via Corticella 183, 40129 Bologna, Italy
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11
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Petrusca L, Croisille P, Augeul L, Ovize M, Mewton N, Viallon M. Cardioprotective effects of shock wave therapy: A cardiac magnetic resonance imaging study on acute ischemia-reperfusion injury. Front Cardiovasc Med 2023; 10:1134389. [PMID: 37180809 PMCID: PMC10172681 DOI: 10.3389/fcvm.2023.1134389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 04/05/2023] [Indexed: 05/16/2023] Open
Abstract
Introduction Cardioprotection strategies remain a new frontier in treating acute myocardial infarction (AMI), aiming at further protect the myocardium from the ischemia-reperfusion damage. Therefore, we aimed at investigating the mechano-transduction effects induced by shock waves (SW) therapy at time of the ischemia reperfusion as a non-invasive cardioprotective innovative approach to trigger healing molecular mechanisms. Methods We evaluated the SW therapy effects in an open-chest pig ischemia-reperfusion (IR) model, with quantitative cardiac Magnetic Resonance (MR) imaging performed along the experiments at multiple time points (baseline (B), during ischemia (I), at early reperfusion (ER) (∼15 min), and late reperfusion (LR) (3 h)). AMI was obtained by a left anterior artery temporary occlusion (50 min) in 18 pigs (32 ± 1.9 kg) randomized into SW therapy and control groups. In the SW therapy group, treatment was started at the end of the ischemia period and extended during early reperfusion (600 + 1,200 shots @0.09 J/mm2, f = 5 Hz). The MR protocol included at all time points LV global function assessment, regional strain quantification, native T1 and T2 parametric mapping. Then, after contrast injection (gadolinium), we obtained late gadolinium imaging and extra-cellular volume (ECV) mapping. Before animal sacrifice, Evans blue dye was administrated after re-occlusion for area-at-risk sizing. Results During ischemia, LVEF decreased in both groups (25 ± 4.8% in controls (p = 0.031), 31.6 ± 3.2% in SW (p = 0.02). After reperfusion, left ventricular ejection fraction (LVEF) remained significantly decreased in controls (39.9 ± 4% at LR vs. 60 ± 5% at baseline (p = 0.02). In the SW group, LVEF increased quickly ER (43.7 ± 11.4% vs. 52.4 ± 8.2%), and further improved at LR (49.4 ± 10.1) (ER vs. LR p = 0.05), close to baseline reference (LR vs. B p = 0.92). Furthermore, there was no significant difference in myocardial relaxation time (i.e. edema) after reperfusion in the intervention group compared to the control group: ΔT1 (MI vs. remote) was increased by 23.2±% for SW vs. +25.2% for the controls, while ΔT2 (MI vs. remote) increased by +24.9% for SW vs. +21.7% for the control group. Discussion In conclusion, we showed in an ischemia-reperfusion open-chest swine model that SW therapy, when applied near the relief of 50' LAD occlusion, led to a nearly immediate cardioprotective effect translating to a reduction in the acute ischemia-reperfusion lesion size and to a significant LV function improvement. These new and promising results related to the multi-targeted effects of SW therapy in IR injury need to be confirmed by further in-vivo studies in close chest models with longitudinal follow-up.
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Affiliation(s)
- Lorena Petrusca
- Univ Lyon, UJM-Saint-Etienne, INSA, CNRS UMR 5520, INSERM U1206, Saint-Etienne, France
| | - Pierre Croisille
- Univ Lyon, UJM-Saint-Etienne, INSA, CNRS UMR 5520, INSERM U1206, Saint-Etienne, France
- Department of Radiology, Centre Hospitalier Universitaire de Saint- Etienne, Université Jean-Monnet, Saint-Etienne, France
| | - Lionel Augeul
- INSERM UMR 1060, CARMEN Laboratory, Université Lyon 1, Faculté de Medecine, Rockfeller, Lyon, France
| | - Michel Ovize
- INSERM UMR 1060, CARMEN Laboratory, Université Lyon 1, Faculté de Medecine, Rockfeller, Lyon, France
- Heart Failure Department, Clinical Investigation Center, Inserm 1407, HCL—Lyon, France
| | - Nathan Mewton
- INSERM UMR 1060, CARMEN Laboratory, Université Lyon 1, Faculté de Medecine, Rockfeller, Lyon, France
- Heart Failure Department, Clinical Investigation Center, Inserm 1407, HCL—Lyon, France
| | - Magalie Viallon
- Univ Lyon, UJM-Saint-Etienne, INSA, CNRS UMR 5520, INSERM U1206, Saint-Etienne, France
- Department of Radiology, Centre Hospitalier Universitaire de Saint- Etienne, Université Jean-Monnet, Saint-Etienne, France
- Correspondence: Magalie Viallon
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12
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Graber M, Nägele F, Röhrs BT, Hirsch J, Pölzl L, Moriggl B, Mayr A, Troger F, Kirchmair E, Wagner JF, Nowosielski M, Mayer L, Voelkl J, Tancevski I, Meyer D, Grimm M, Knoflach M, Holfeld J, Gollmann-Tepeköylü C. Prevention of Oxidative Damage in Spinal Cord Ischemia Upon Aortic Surgery: First-In-Human Results of Shock Wave Therapy Prove Safety and Feasibility. J Am Heart Assoc 2022; 11:e026076. [PMID: 36216458 DOI: 10.1161/jaha.122.026076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Spinal cord ischemia (SCI) remains a devastating complication after aortic dissection or repair. A primary hypoxic damage is followed by a secondary damage resulting in further cellular loss via apoptosis. Affected patients have a poor prognosis and limited therapeutic options. Shock wave therapy (SWT) improves functional outcome, neuronal degeneration and survival in murine spinal cord injury. In this first-in-human study we treated 5 patients with spinal cord ischemia with SWT aiming to prove safety and feasibility. Methods and Results Human neurons were subjected to ischemic injury with subsequent SWT. Reactive oxygen species and cellular apoptosis were quantified using flow cytometry. Signaling of the antioxidative transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) and immune receptor Toll-like receptor 3 (TLR3) were analyzed. To assess whether SWT act via a conserved mechanism, transgenic tlr3-/- zebrafish created via CRISPR/Cas9 were subjected to spinal cord injury. To translate our findings into a clinical setting, 5 patients with SCI underwent SWT. Baseline analysis and follow-up (6 months) included assessment of American Spinal Cord Injury Association (ASIA) impairment scale, evaluation of Spinal Cord Independence Measure score and World Health Organization Quality of Life questionnaire. SWT reduced the number of reactive oxygen species positive cells and apoptosis upon ischemia via induction of the antioxidative factor nuclear factor erythroid 2-related factor 2. Inhibition or deletion of tlr3 impaired axonal growth after spinal cord lesion in zebrafish, whereas tlr3 stimulation enhanced spinal regeneration. In a first-in-human study, we treated 5 patients with SCI using SWT (mean age, 65.3 years). Four patients presented with acute aortic dissection (80%), 2 of them exhibited preoperative neurological symptoms (40%). Impairment was ASIA A in 1 patient (20%), ASIA B in 3 patients (60%), and ASIA D in 1 patient (20%) at baseline. At follow-up, 2 patients were graded as ASIA A (40%) and 3 patients as ASIA B (60%). Spinal cord independence measure score showed significant improvement. Examination of World Health Organization Quality of Life questionnaires revealed increased scores at follow-up. Conclusions SWT reduces oxidative damage upon SCI via immune receptor TLR3. The first-in-human application proved safety and feasibility in patients with SCI. SWT could therefore become a powerful regenerative treatment option for this devastating injury.
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Affiliation(s)
- Michael Graber
- Department of Cardiac Surgery Medical University of Innsbruck Austria
| | - Felix Nägele
- Department of Cardiac Surgery Medical University of Innsbruck Austria
| | | | - Jakob Hirsch
- Department of Cardiac Surgery Medical University of Innsbruck Austria
| | - Leo Pölzl
- Department of Cardiac Surgery Medical University of Innsbruck Austria
| | - Bernhard Moriggl
- Division of Clinical and Functional Anatomy Medical University of Innsbruck Austria
| | - Agnes Mayr
- Department of Radiology Medical University of Innsbruck Austria
| | - Felix Troger
- Department of Radiology Medical University of Innsbruck Austria
| | - Elke Kirchmair
- Department of Cardiac Surgery Medical University of Innsbruck Austria
| | | | | | - Lukas Mayer
- Department of Neurology Medical University of Innsbruck Austria
| | - Jakob Voelkl
- Institute for Physiology and Pathophysiology Johannes Kepler University Linz Linz Austria.,Department of Nephrology and Medical Intensive Care Charité-Universitätsmedizin Berlin Berlin Germany.,DZHK (German Centre for Cardiovascular Research) Partner Site Berlin Berlin Germany
| | - Ivan Tancevski
- Department of Internal Medicine II Medical University of Innsbruck Austria
| | - Dirk Meyer
- Institute of Molecular Biology/CMBI University of Innsbruck Austria
| | - Michael Grimm
- Department of Cardiac Surgery Medical University of Innsbruck Austria
| | | | - Johannes Holfeld
- Department of Cardiac Surgery Medical University of Innsbruck Austria
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13
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Guo J, Hai H, Ma Y. Application of extracorporeal shock wave therapy in nervous system diseases: A review. Front Neurol 2022; 13:963849. [PMID: 36062022 PMCID: PMC9428455 DOI: 10.3389/fneur.2022.963849] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 07/21/2022] [Indexed: 11/29/2022] Open
Abstract
Neurological disorders are one of the leading causes of morbidity and mortality worldwide, and their therapeutic options remain limited. Recent animal and clinical studies have shown the potential of extracorporeal shock wave therapy (ESWT) as an innovative, safe, and cost-effective option to treat neurological disorders. Moreover, the cellular and molecular mechanism of ESWT has been proposed to better understand the regeneration and repairment of neurological disorders by ESWT. In this review, we discuss the principles of ESWT, the animal and clinical studies involving the use of ESWT to treat central and peripheral nervous system diseases, and the proposed cellular and molecular mechanism of ESWT. We also discuss the challenges encountered when applying ESWT to the human brain and spinal cord and the new potential applications of ESWT in treating neurological disorders.
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14
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Ditac G, Bessière F, Lafon C. Therapeutic ultrasound applications in cardiovascular diseases: a review. Ing Rech Biomed 2022. [DOI: 10.1016/j.irbm.2022.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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15
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Graber M, Nägele F, Hirsch J, Pölzl L, Schweiger V, Lechner S, Grimm M, Cooke JP, Gollmann-Tepeköylü C, Holfeld J. Cardiac Shockwave Therapy – A Novel Therapy for Ischemic Cardiomyopathy? Front Cardiovasc Med 2022; 9:875965. [PMID: 35647069 PMCID: PMC9133452 DOI: 10.3389/fcvm.2022.875965] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/12/2022] [Indexed: 11/14/2022] Open
Abstract
Over the past decades, shockwave therapy (SWT) has gained increasing interest as a therapeutic approach for regenerative medicine applications, such as healing of bone fractures and wounds. More recently, pre-clinical studies have elucidated potential mechanisms for the regenerative effects of SWT in myocardial ischemia. The mechanical stimulus of SWT may induce regenerative effects in ischemic tissue via growth factor release, modulation of inflammatory response, and angiogenesis. Activation of the innate immune system and stimulation of purinergic receptors by SWT appears to enhance vascularization and regeneration of injured tissue with functional improvement. Intriguingly, small single center studies suggest that SWT may improve angina, exercise tolerance, and hemodynamics in patients with ischemic heart disease. Thus, SWT may represent a promising technology to induce cardiac protection or repair in patients with ischemic heart disease.
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Affiliation(s)
- Michael Graber
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States
| | - Felix Nägele
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Jakob Hirsch
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Leo Pölzl
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
- Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Innsbruck, Austria
| | - Victor Schweiger
- Department of Cardiology, University Hospital Zurich, Zurich, Switzerland
| | - Sophia Lechner
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael Grimm
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - John P. Cooke
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States
| | | | - Johannes Holfeld
- Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
- *Correspondence: Johannes Holfeld,
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16
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Zaccagnini G, Greco S, Voellenkle C, Gaetano C, Martelli F. miR-210 hypoxamiR in Angiogenesis and Diabetes. Antioxid Redox Signal 2022; 36:685-706. [PMID: 34521246 DOI: 10.1089/ars.2021.0200] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: microRNA-210 (miR-210) is the master hypoxia-inducible miRNA (hypoxamiR) since it has been found to be significantly upregulated under hypoxia in a wide range of cell types. Recent advances: Gene ontology analysis of its targets indicates that miR-210 modulates several aspects of cellular response to hypoxia. Due to its high pleiotropy, miR-210 not only plays a protective role by fine-tuning mitochondrial metabolism and inhibiting red-ox imbalance and apoptosis, but it can also promote cell proliferation, differentiation, and migration, substantially contributing to angiogenesis. Critical issues: As most miRNAs, modulating different gene pathways, also miR-210 can potentially lead to different and even opposite effects, depending on the physio-pathological contexts in which it acts. Future direction: The use of miRNAs as therapeutics is a fast growing field. This review aimed at highlighting the role of miR-210 in angiogenesis in the context of ischemic cardiovascular diseases and diabetes in order to clarify the molecular mechanisms underpinning miR-210 action. Particular attention will be dedicated to experimentally validated miR-210 direct targets involved in cellular processes related to angiogenesis and diabetes mellitus, such as mitochondrial metabolism, redox balance, apoptosis, migration, and adhesion. Antioxid. Redox Signal. 36, 685-706.
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Affiliation(s)
- Germana Zaccagnini
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Simona Greco
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Christine Voellenkle
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Carlo Gaetano
- Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
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17
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Kudo N. Shock wave lithotripsy and therapy. J Med Ultrason (2001) 2022:10.1007/s10396-022-01202-w. [PMID: 35347482 DOI: 10.1007/s10396-022-01202-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/28/2022] [Indexed: 10/18/2022]
Abstract
The biological effects of ultrasound exposure are classified into thermal and mechanical effects. The medical application of shock waves has been explored widely as a technique that exerts a mechanical effect with no thermal effect on the living body. The application of shock waves started in urology as a method to disintegrate calculi by impulsive force. During widespread use in urology, it was confirmed that shock waves could also induce some changes in the bones and soft tissues located in the propagation path, and application of shock waves in the field of orthopedics is currently under intensive investigation. In this brief review, we first discuss the similarities of and differences between shock waves and ultrasound. The characteristics of shock wave sources used to generate therapeutic shock waves are then described, and the mechanisms by which shock waves induce stone fragmentation and other therapeutic effects are discussed.
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Affiliation(s)
- Nobuki Kudo
- Faculty of Information Science and Technology, Hokkaido University, N14W9, Kita-ku, Sapporo, 060-0814, Japan.
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18
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Yang D, Wang M, Hu Z, Ma Y, Shi Y, Cao X, Guo T, Cai H, Cai H. Extracorporeal Cardiac Shock Wave-Induced Exosome Derived From Endothelial Colony-Forming Cells Carrying miR-140-3p Alleviate Cardiomyocyte Hypoxia/Reoxygenation Injury via the PTEN/PI3K/AKT Pathway. Front Cell Dev Biol 2022; 9:779936. [PMID: 35083214 PMCID: PMC8784835 DOI: 10.3389/fcell.2021.779936] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/30/2021] [Indexed: 11/28/2022] Open
Abstract
Background: Stem cell-derived exosomes have great potential in the treatment of myocardial ischemia–reperfusion injury (IRI). Extracorporeal cardiac shock waves (ECSW) as effective therapy, in part, could activate the function of exosomes. In this study, we explored the effect of ECSW-induced exosome derived from endothelial colony-forming cells on cardiomyocyte hypoxia/reoxygenation (H/R) injury and its underlying mechanisms. Methods: The exosomes were extracted and purified from the supernatant of endothelial colony-forming cells (ECFCs-exo). ECFCs-exo treated with shock wave (SW-exo) or without shock wave (CON-exo) were performed with high-throughput sequencing of the miRNA. H9c2 cells were incubated with SW-exo or CON-exo after H/R injury. The cell viability, cell apoptosis, oxidative stress level, and inflammatory factor were assessed. qRT-PCR was used to detect the expression levels of miRNA and mRNA in cells and exosomes. The PTEN/PI3K/AKT pathway-related proteins were detected by Western blotting, respectively. Results: Exosomes secreted by ECFCs could be taken up by H9c2 cells. Administration of SW-exo to H9c2 cells after H/R injury could significantly improve cell viability, inhibit cell apoptosis, and downregulate oxidative stress level (p < 0.01), with an increase in Bcl-2 protein and a decrease in Bax, cleaved caspase-3, and NF-κB protein (p < 0.05). Notably, miR-140-3p was found to be highly enriched both in ECFCs and ECFCs-exo treated with ECSW (p < 0.05) and served as a critical mediator. SW-exo increased miR-140-3p expression but decreased PTEN expression in H9c2 cells with enhanced phosphorylation of the PI3K/AKT signaling pathway. These cardioprotective effects of SW-exo on H/R injury were blunted by the miR-140-3p inhibitor. Dual-luciferase assay verified that miR-140-3p could directly target the 3′UTR of PTEN mRNA and exert a negative regulatory effect. Conclusion: This study has shown the potential of ECSW as an effective stimulation for the exosomes derived from ECFCs in vitro. SW-exo exerted a stronger therapeutic effect on H/R injury in H9c2 cells possibly via delivering exosomal miR-140-3p, which might be a novel promising strategy for the myocardial IRI.
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Affiliation(s)
- Dan Yang
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Mingqiang Wang
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhao Hu
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yiming Ma
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yunke Shi
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xingyu Cao
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Tao Guo
- Department of Cardiology, Yunnan Fuwai Cardiovascular Hospital, Kunming, China
| | - Hongbo Cai
- Department of Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hongyan Cai
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
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19
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Wang M, Yang D, Hu Z, Shi Y, Ma Y, Cao X, Guo T, Cai H, Cai H. Extracorporeal Cardiac Shock Waves Therapy Improves the Function of Endothelial Progenitor Cells After Hypoxia Injury via Activating PI3K/Akt/eNOS Signal Pathway. Front Cardiovasc Med 2021; 8:747497. [PMID: 34708093 PMCID: PMC8542843 DOI: 10.3389/fcvm.2021.747497] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/13/2021] [Indexed: 01/05/2023] Open
Abstract
Background: Extracorporeal cardiac shock waves (ECSW) have great potential in the treatment of coronary heart disease. Endothelial progenitor cells (EPCs) are a class of pluripotent progenitor cells derived from bone marrow or peripheral blood, which have the capacity to migrate to ischemic myocardium and differentiate into mature endothelial cells and play an important role in neovascularization and endothelial repair. In this study, we investigated whether ECSW therapy can improve EPCs dysfunction and apoptosis induced by hypoxia and explored the underlying mechanisms. Methods: EPCs were separated from ApoE gene knockout rat bone marrow and identified using flow cytometry and fluorescence staining. EPCs were used to produce in vitro hypoxia-injury models which were then divided into six groups: Control, Hypoxia, Hypoxia + ECSW, Hypoxia + LY294002 + ECSW, Hypoxia + MK-2206 + ECSW, and Hypoxia + L-NAME + ECSW. EPCs from the Control, Hypoxia, and Hypoxia + ECSW groups were used in mRNA sequencing reactions. mRNA and protein expression levels were analyzed using qRT-PCR and western blot analysis, respectively. Proliferation, apoptosis, adhesion, migration, and angiogenesis were measured using CCK-8, flow cytometry, gelatin, transwell, and tube formation, respectively. Nitric oxide (NO) levels were measured using an NO assay kit. Results: Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that differentially expressed genes were enriched in cancer signaling, PI3K-Akt signaling, and Rap1 signaling pathways. We selected differentially expressed genes in the PI3K-Akt signaling pathway and verified them using a series of experiments. The results showed that ECSW therapy (500 shots at 0.09 mJ/mm2) significantly improved proliferation, adhesion, migration, and tube formation abilities of EPCs following hypoxic injury, accompanied by upregulation of p-PI3K, p-Akt, p-eNOS, Bcl-2 protein and NO, PI3K, and Akt mRNA expression, and downregulation of Bax and Caspase3 protein expression. All these effects of ECSW were eliminated using inhibitors specific to PI3K (LY294002), Akt (MK-2206), and eNOS (L-NAME). Conclusion: ECSW exerted a strong repaired effect on EPCs suffering inhibited hypoxia injury by inhibiting cell apoptosis and promoting angiogenesis, mainly through activating the PI3K/Akt/eNOS signaling pathway, which provide new evidence for ECSW therapy in CHD.
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Affiliation(s)
- Mingqiang Wang
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Dan Yang
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhao Hu
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yunke Shi
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yiming Ma
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xingyu Cao
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Tao Guo
- Department of Cardiology, Yunnan Fuwai Cardiovascular Hospital, Kunming, China
| | - Hongbo Cai
- Department of Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hongyan Cai
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
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20
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Skov-Jeppesen SM, Yderstraede KB, Jensen BL, Bistrup C, Hanna M, Lund L. Low-Intensity Shockwave Therapy (LI-ESWT) in Diabetic Kidney Disease: Results from an Open-Label Interventional Clinical Trial. Int J Nephrol Renovasc Dis 2021; 14:255-266. [PMID: 34285548 PMCID: PMC8286109 DOI: 10.2147/ijnrd.s315143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/04/2021] [Indexed: 01/07/2023] Open
Abstract
Purpose Treatment with low-intensity shockwave therapy (LI-ESWT) is associated with angiogenesis and is suggested as a treatment for different types of vascular diseases. It was hypothesized that LI-ESWT improves the renal filtration barrier and halts the progression of GFR decline in diabetic kidney disease (DKD) potentially through VEGF and NO formation. We present the first data on LI-ESWT in human DKD. Methods The study was designed as an interventional, prospective, one-arm, Phase 1 study. We investigated change in GFR and albuminuria in 28 patients with DKD treated with six sessions of LI-ESWT over three weeks. The patients were followed for six months. Urine excretion of kidney injury markers, vascular endothelial growth factor (VEGF) and nitric oxide metabolites (NOx) was studied after LI-ESWT. Results There were no significant changes in GFR and albuminuria up to six months after LI-ESWT compared to baseline. Urine VEGF was transiently reduced one month after LI-ESWT, but there were no other significant changes in urine VEGF or NOx after LI-ESWT. Secondary analysis showed that NOx increased after LI-ESWT in patients who had low levels of NOx at baseline. Kidney injury marker trefoil factor 3 (TFF3) increased acutely after the first session of LI-ESWT indicating transient endothelial repair. Other markers of kidney injury were stable in relation to LI-ESWT. Conclusion LI-ESWT treatment did not significantly improve kidney function and albumin excretion. It is concluded that LI-ESWT is not harmful. A randomized blinded study should be performed to clarify whether adjunctive treatment with LI-ESWT is superior to standard treatment of DKD.
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Affiliation(s)
- Sune Moeller Skov-Jeppesen
- Department of Urology, Odense University Hospital, Odense, Denmark.,OPEN, Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark.,Clinical Institute, University of Southern Denmark, Odense, Denmark
| | - Knud Bonnet Yderstraede
- Clinical Institute, University of Southern Denmark, Odense, Denmark.,Department of Endocrinology, Odense University Hospital, Odense, Denmark
| | - Boye L Jensen
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Claus Bistrup
- Clinical Institute, University of Southern Denmark, Odense, Denmark.,Department of Nephrology, Odense University Hospital, Odense, Denmark
| | - Milad Hanna
- Department of Urology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Lars Lund
- Department of Urology, Odense University Hospital, Odense, Denmark.,Clinical Institute, University of Southern Denmark, Odense, Denmark
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21
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Imashiro C, Azuma T, Itai S, Kuribara T, Totani K, Onoe H, Takemura K. Travelling ultrasound promotes vasculogenesis of three-dimensional-monocultured human umbilical vein endothelial cells. Biotechnol Bioeng 2021; 118:3760-3769. [PMID: 34110012 PMCID: PMC8518538 DOI: 10.1002/bit.27852] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 05/05/2021] [Accepted: 06/07/2021] [Indexed: 12/31/2022]
Abstract
To generate three‐dimensional tissue in vitro, promoting vasculogenesis in cell aggregates is an important factor. Here, we found that ultrasound promoted vasculogenesis of human umbilical vein endothelial cells (HUVECs). Promotion of HUVEC network formation and lumen formation were observed using our method. In addition to morphological evaluations, protein expression was quantified by western blot assays. As a result, expression of proteins related to vasculogenesis and the response to mechanical stress on cells was enhanced by exposure to ultrasound. Although several previous studies have shown that ultrasound may promote vasculogenesis, the effect of ultrasound was unclear because of unregulated ultrasound, the complex culture environment, or two‐dimensional‐cultured HUVECs that cannot form a lumen structure. In this study, regulated ultrasound was propagated on three‐dimensional‐monocultured HUVECs, which clarified the effect of ultrasound on vasculogenesis. We believe this finding may be an innovation in the tissue engineering field.
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Affiliation(s)
- Chikahiro Imashiro
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Shinjuku-ku, Japan.,Department of Mechanical Engineering, Keio University, Yokohama, Kohoku-ku, Japan
| | - Tetsuya Azuma
- Department of Mechanical Engineering, Keio University, Yokohama, Kohoku-ku, Japan
| | - Shun Itai
- School of Integrated Design Engineering, Graduate School of Science and Technology, Keio University, Yokohama, Kohoku-ku, Japan
| | - Taiki Kuribara
- Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, Tokyo, Musashino-shi, Japan
| | - Kiichiro Totani
- Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, Tokyo, Musashino-shi, Japan
| | - Hiroaki Onoe
- Department of Mechanical Engineering, Keio University, Yokohama, Kohoku-ku, Japan
| | - Kenjiro Takemura
- Department of Mechanical Engineering, Keio University, Yokohama, Kohoku-ku, Japan
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22
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Zhao Y, Santelli A, Zhu XY, Zhang X, Woollard JR, Chen XJ, Jordan KL, Krier J, Tang H, Saadiq I, Lerman A, Lerman LO. Low-Energy Shockwave Treatment Promotes Endothelial Progenitor Cell Homing to the Stenotic Pig Kidney. Cell Transplant 2021; 29:963689720917342. [PMID: 32237997 PMCID: PMC7444225 DOI: 10.1177/0963689720917342] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Endothelial progenitor cells (EPCs) patrols the circulation and contributes to
endothelial cell regeneration. Atherosclerotic renal artery stenosis (ARAS)
induces microvascular loss in the stenotic kidney (STK). Low-energy shockwave
therapy (SW) can induce angiogenesis and restore the STK microcirculation, but
the underlying mechanism remains unclear. We tested the hypothesis that SW
increases EPC homing to the swine STK, associated with capillary regeneration.
Normal pigs and pigs after 3 wk of renal artery stenosis were treated with six
sessions of low-energy SW (biweekly for three consecutive weeks) or left
untreated. Four weeks after completion of treatment, we assessed EPC
(CD34+/KDR+) numbers and levels of the homing-factor stromal cell-derived factor
(SDF)-1 in the inferior vena cava and the STK vein and artery, as well as
urinary levels of vascular endothelial growth factor (VEGF) and integrin-1β.
Subsequently, we assessed STK morphology, capillary count, and expression of the
proangiogenic growth factors angiopoietin-1, VEGF, and endothelial nitric oxide
synthase ex vivo. A 3-wk low-energy SW regimen improved STK
structure, capillary count, and function in ARAS+SW, and EPC numbers and
gradients across the STK decreased. Plasma SDF-1 and renal expression of
angiogenic factors were increased in ARAS+SW, and urinary levels of VEGF and
integrin-1β tended to rise during the SW regimen. In conclusion, SW improves
ischemic kidney capillary density, which is associated with, and may be at least
in part mediated by, promoting EPCs mobilization and homing to the stenotic
kidney.
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Affiliation(s)
- Yu Zhao
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.,Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, China.,* Both the authors contributed equally to this article
| | - Adrian Santelli
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.,* Both the authors contributed equally to this article
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Xin Zhang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - John R Woollard
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Xiao-Jun Chen
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Kyra L Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - James Krier
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Ishran Saadiq
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
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23
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Defining a therapeutic range for regeneration of ischemic myocardium via shock waves. Sci Rep 2021; 11:409. [PMID: 33432034 PMCID: PMC7801389 DOI: 10.1038/s41598-020-79776-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 12/14/2020] [Indexed: 12/04/2022] Open
Abstract
Shockwave therapy (SWT) represents a promising regenerative treatment option for patients with ischemic cardiomyopathy. Although no side-effects have been described upon SWT, potential cellular damage at therapeutic energies has not been addressed so far. In this work, we aimed to define a therapeutic range for shock wave application for myocardial regeneration. We could demonstrate that SWT does not induce cellular damage beneath energy levels of 0.27 mJ/mm2 total flux density. Endothelial cell proliferation, angiogenic gene expression and phosphorylation of AKT and ERK are enhanced in a dose dependent manner until 0.15 mJ/mm2 energy flux density. SWT induces regeneration of ischemic muscle in vivo via expression of angiogenic gene expression, enhanced neovascularization and improved limb perfusion in a dose-dependent manner. Therefore, we provide evidence for a dose-dependent induction of angiogenesis after SWT, as well as the absence of cellular damage upon SWT within the therapeutic range. These data define for the first time a therapeutic range of SWT, a promising regenerative treatment option for ischemic cardiomyopathy.
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24
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Abstract
Chronic kidney disease is a global health care burden, yet clinically-proven treatments are limited. Low-intensity shockwave, which utilizes ≈10% of the energy levels used in clinically indicated shockwave lithotripsy, is a promising technique to ameliorate ischemia and regenerate tissues. It has been demonstrated to improve healing in tissues such as bone, muscle, myocardium, and kidney via several mechanisms, particularly through promoting neovascularization. Low-intensity shockwave stimulates mechanoreceptors located primarily in endothelial and proximal tubular cells and subsequently upregulates vascular endothelial growth factors. This, in turn, promotes angiogenesis and ameliorates renal hypoxia, inflammation, and fibrosis, and ultimately preserves renal function. Furthermore, low-intensity shockwave can stimulate release of homing factors to attract endothelial progenitor or stem cells into injured kidneys for tissue repair. These effects may be beneficial in several kidney disease models, including renal artery stenosis, diabetic kidney disease, and various chronic kidney diseases, although most studies reported to date have been performed in animal models. Because of its low energy intensity, the procedure is relatively tolerable and safe, yet, more clinical studies are needed to establish its efficacy beyond currently existing strategies. Therefore, low-intensity shockwave therapy emerges as an alternative therapeutic approach that may offer a promising noninvasive intervention for treating renal diseases. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02515461; NCT03602807; and NCT03445247.
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Affiliation(s)
- Nattawat Klomjit
- From the Division of Nephrology and Hypertension (N.K., L.O.L.), Mayo Clinic, Rochester, MN
| | - Amir Lerman
- Department of Cardiovascular Disease (A.L.), Mayo Clinic, Rochester, MN
| | - Lilach O Lerman
- From the Division of Nephrology and Hypertension (N.K., L.O.L.), Mayo Clinic, Rochester, MN
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25
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Large Animal Models of Cell-Free Cardiac Regeneration. Biomolecules 2020; 10:biom10101392. [PMID: 33003617 PMCID: PMC7600588 DOI: 10.3390/biom10101392] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 09/23/2020] [Accepted: 09/27/2020] [Indexed: 12/13/2022] Open
Abstract
The adult mammalian heart lacks the ability to sufficiently regenerate itself, leading to the progressive deterioration of function and heart failure after ischemic injuries such as myocardial infarction. Thus far, cell-based therapies have delivered unsatisfactory results, prompting the search for cell-free alternatives that can induce the heart to repair itself through cardiomyocyte proliferation, angiogenesis, and advantageous remodeling. Large animal models are an invaluable step toward translating basic research into clinical applications. In this review, we give an overview of the state-of-the-art in cell-free cardiac regeneration therapies that have been tested in large animal models, mainly pigs. Cell-free cardiac regeneration therapies involve stem cell secretome- and extracellular vesicles (including exosomes)-induced cardiac repair, RNA-based therapies, mainly regarding microRNAs, but also modified mRNA (modRNA) as well as other molecules including growth factors and extracellular matrix components. Various methods for the delivery of regenerative substances are used, including adenoviral vectors (AAVs), microencapsulation, and microparticles. Physical stimulation methods and direct cardiac reprogramming approaches are also discussed.
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26
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Lu CC, Chou SH, Shen PC, Chou PH, Ho ML, Tien YC. Extracorporeal shock wave promotes activation of anterior cruciate ligament remnant cells and their paracrine regulation of bone marrow stromal cells' proliferation, migration, collagen synthesis, and differentiation. Bone Joint Res 2020; 9:458-468. [PMID: 32832074 PMCID: PMC7418778 DOI: 10.1302/2046-3758.98.bjr-2019-0365.r1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Aims Proliferation, migration, and differentiation of anterior cruciate ligament (ACL) remnant and surrounding cells are fundamental processes for ACL reconstruction; however, the interaction between ACL remnant and surrounding cells is unclear. We hypothesized that ACL remnant cells preserve the capability to regulate the surrounding cells' activity, collagen gene expression, and tenogenic differentiation. Moreover, extracorporeal shock wave (ESW) would not only promote activity of ACL remnant cells, but also enhance their paracrine regulation of surrounding cells. Methods Cell viability, proliferation, migration, and expression levels of Collagen-I (COL-I) A1, transforming growth factor beta (TGF-β), and vascular endothelial growth factor (VEGF) were compared between ACL remnant cells untreated and treated with ESW (0.15 mJ/mm2, 1,000 impulses, 4 Hz). To evaluate the subsequent effects on the surrounding cells, bone marrow stromal cells (BMSCs)' viability, proliferation, migration, and levels of Type I Collagen, Type III Collagen, and tenogenic gene (Scx, TNC) expression were investigated using coculture system. Results ESW-treated ACL remnant cells presented higher cell viability, proliferation, migration, and increased expression of COL-I A1, TGF-β, and VEGF. BMSC proliferation and migration rate significantly increased after coculture with ACL remnant cells with and without ESW stimulation compared to the BMSCs alone group. Furthermore, ESW significantly enhanced ACL remnant cells' capability to upregulate the collagen gene expression and tenogenic differentiation of BMSCs, without affecting cell viability, TGF-β, and VEGF expression. Conclusion ACL remnant cells modulated activity and differentiation of surrounding cells. The results indicated that ESW enhanced ACL remnant cells viability, proliferation, migration, and expression of collagen, TGF-β, VEGF, and paracrine regulation of BMSC proliferation, migration, collagen expression, and tenogenesis.Cite this article: Bone Joint Res 2020;9(8):458-468.
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Affiliation(s)
- Cheng-Chang Lu
- Department of Orthopedics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shih-Hsiang Chou
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Chih Shen
- Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Hsi Chou
- Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mei-Ling Ho
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yin-Chun Tien
- Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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27
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Gollmann-Tepeköylü C, Nägele F, Graber M, Pölzl L, Lobenwein D, Hirsch J, An A, Irschick R, Röhrs B, Kremser C, Hackl H, Huber R, Venezia S, Hercher D, Fritsch H, Bonaros N, Stefanova N, Tancevski I, Meyer D, Grimm M, Holfeld J. Shock waves promote spinal cord repair via TLR3. JCI Insight 2020; 5:134552. [PMID: 32759498 DOI: 10.1172/jci.insight.134552] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 06/24/2020] [Indexed: 01/16/2023] Open
Abstract
Spinal cord injury (SCI) remains a devastating condition with poor prognosis and very limited treatment options. Affected patients are severely restricted in their daily activities. Shock wave therapy (SWT) has shown potent regenerative properties in bone fractures, wounds, and ischemic myocardium via activation of the innate immune receptor TLR3. Here, we report on the efficacy of SWT for regeneration of SCI. SWT improved motor function and decreased lesion size in WT but not Tlr3-/- mice via inhibition of neuronal degeneration and IL6-dependent recruitment and differentiation of neuronal progenitor cells. Both SWT and TLR3 stimulation enhanced neuronal sprouting and improved neuronal survival, even in human spinal cord cultures. We identified tlr3 as crucial enhancer of spinal cord regeneration in zebrafish. Our findings indicate that TLR3 signaling is involved in neuroprotection and spinal cord repair and suggest that TLR3 stimulation via SWT could become a potent regenerative treatment option.
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Affiliation(s)
| | | | - Michael Graber
- Department of Cardiac Surgery and.,Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Innsbruck, Austria
| | - Leo Pölzl
- Department of Cardiac Surgery and.,Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Innsbruck, Austria
| | - Daniela Lobenwein
- Department of Cardiac Surgery and.,Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Innsbruck, Austria
| | | | | | - Regina Irschick
- Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Innsbruck, Austria
| | - Bernhard Röhrs
- Institute of Molecular Biology/Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | | | | | | | - Serena Venezia
- Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - David Hercher
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Helga Fritsch
- Division of Clinical and Functional Anatomy, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Nadia Stefanova
- Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Ivan Tancevski
- Department of Internal Medicine II, Infectious Diseases, Pneumology, Rheumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Dirk Meyer
- Institute of Molecular Biology/Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | | | - Johannes Holfeld
- Department of Cardiac Surgery and.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
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28
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Ma Y, Hu Z, Yang D, Li L, Wang L, Xiao J, Cao X, Shi Y, Cai H. Extracorporeal cardiac shock waves therapy promotes function of endothelial progenitor cells through PI3K/AKT and MEK/ERK signaling pathways. Am J Transl Res 2020; 12:3895-3905. [PMID: 32774743 PMCID: PMC7407747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 06/03/2020] [Indexed: 06/11/2023]
Abstract
Previous studies have demonstrated extracorporeal cardiac shock waves (ECSW) could induce angiogenesis and improves myocardial function in patients with coronary heart diseases as a safe, effective, and non-invasive angiogenic approach. The endothelial progenitor cells (EPCs) can migrate to the ischemic myocardium and differentiate into vascular endothelial cells, thus promoting the angiogenesis. Whether ECSW can improve the angiogenic ability of EPCs is unclear. This topic studied the effects of ECSW Therapy on EPCs functions and related signal transduction pathways. The bone marrow-derived EPCs of SD rats were isolated by the density centrifugation method. After treatment with ECSW (500 shots at 0.09 mJ/mm2), the cell viability, anti-apoptosis, migration, and tube formation of EPCs were significantly improved. In addition, the expressions of phosphorylated AKT and ERK were increased after ECSW treatment, the expressions of downstream signaling molecules eNOS and Bcl-2 were also increased, but the expressions of Bax and Caspase3 were decreased. However, these beneficial effects can be inhibited by PI3K/AKT inhibitor LY294002 and MEK/ERK inhibitor PD98059. Together, ECSW can promote the cell viability, migration, and angiogenic ability of EPCs and inhibit the apoptosis of EPCs through the PI3K/AKT and MEK/ERK signaling pathways. The mechanism may be related to promoting the expressions of downstream p-eNOS and anti-apoptotic protein Bcl-2 and inhibiting the expressions of pro-apoptotic protein Bax and Caspase3 through the PI3K/AKT and MEK/ERK signaling pathways.
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Affiliation(s)
- Yiming Ma
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University Kunming, China
| | - Zhao Hu
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University Kunming, China
| | - Dan Yang
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University Kunming, China
| | - Li Li
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University Kunming, China
| | - Luqiao Wang
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University Kunming, China
| | - Jianming Xiao
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University Kunming, China
| | - Xingyu Cao
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University Kunming, China
| | - Yunke Shi
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University Kunming, China
| | - Hongyan Cai
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University Kunming, China
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29
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Basoli V, Chaudary S, Cruciani S, Santaniello S, Balzano F, Ventura C, Redl H, Dungel P, Maioli M. Mechanical Stimulation of Fibroblasts by Extracorporeal Shock Waves: Modulation of Cell Activation and Proliferation Through a Transient Proinflammatory Milieu. Cell Transplant 2020; 29:963689720916175. [PMID: 32326741 PMCID: PMC7586264 DOI: 10.1177/0963689720916175] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/21/2020] [Accepted: 03/03/2020] [Indexed: 12/14/2022] Open
Abstract
Extracorporeal shock waves (ESWTs) are "mechanical" waves, widely used in regenerative medicine, including soft tissue wound repair. Although already being used in the clinical practice, the mechanism of action underlying their biological activities is still not fully understood. In the present paper we tried to elucidate whether a proinflammatory effect may contribute to the regenerative potential of shock waves treatment. For this purpose, we exposed human foreskin fibroblasts (HFF1 cells) to an ESWT treatment (100 pulses using energy flux densities of 0.19 mJ/mm2 at 3 Hz), followed by cell analyses after 5 min, up to 48 h. We then evaluated cell proliferation, reactive oxygen species generation, ATP release, and cytokine production. Cells cultured in the presence of lipopolysaccharide (LPS), to induce inflammation, were used as a positive control, indicating that LPS-mediated induction of a proinflammatory pattern in HFF1 increased their proliferation. Here, we provide evidence that ESWTs affected fibroblast proliferation through the overexpression of selected cytokines involved in the establishment of a proinflammatory program, superimposable to what was observed in LPS-treated cells. The possibility that inflammatory circuits can be modulated by ESWT mechanotransduction may disclose novel hypothesis on their biological underpinning and expand the fields of their biomedical application.
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Affiliation(s)
- Valentina Basoli
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems – Eldor Lab, Innovation Accelerator, CNR, Bologna, Italy
| | - Sidrah Chaudary
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Allgemeine Unfallversicherungsanstalt (AUVA) Research Centre, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems – Eldor Lab, Innovation Accelerator, CNR, Bologna, Italy
| | - Sara Santaniello
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems – Eldor Lab, Innovation Accelerator, CNR, Bologna, Italy
| | - Francesca Balzano
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Carlo Ventura
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems – Eldor Lab, Innovation Accelerator, CNR, Bologna, Italy
| | - Heniz Redl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Allgemeine Unfallversicherungsanstalt (AUVA) Research Centre, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Peter Dungel
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Allgemeine Unfallversicherungsanstalt (AUVA) Research Centre, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems – Eldor Lab, Innovation Accelerator, CNR, Bologna, Italy
- Center for Developmental Biology and Reprogramming- CEDEBIOR, Department of Biomedical Sciences, University of Sassari, Sassari, Italy
- Institute for Genetic and Biomedical Research, National Research Council (CNR), Monserrato, Cagliari, Italy
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30
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Gollmann-Tepeköylü C, Lobenwein D, Theurl M, Primessnig U, Lener D, Kirchmair E, Mathes W, Graber M, Pölzl L, An A, Koziel K, Pechriggl E, Voelkl J, Paulus P, Schaden W, Grimm M, Kirchmair R, Holfeld J. Shock Wave Therapy Improves Cardiac Function in a Model of Chronic Ischemic Heart Failure: Evidence for a Mechanism Involving VEGF Signaling and the Extracellular Matrix. J Am Heart Assoc 2019; 7:e010025. [PMID: 30371289 PMCID: PMC6474945 DOI: 10.1161/jaha.118.010025] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Mechanical stimulation of acute ischemic myocardium by shock wave therapy (SWT) is known to improve cardiac function by induction of angiogenesis. However, SWT in chronic heart failure is poorly understood. We aimed to study whether mechanical stimulation upon SWT improves heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis and to dissect underlying mechanisms. Methods and Results SWT was applied in a mouse model of chronic myocardial ischemia. To study effects of SWT on postnatal vasculogenesis, wild‐type mice received bone marrow transplantation from green fluorescence protein donor mice. Underlying mechanisms were elucidated in vitro in endothelial cells and murine aortic rings. Echocardiography and pressure/volume measurements revealed improved left ventricular ejection fraction, myocardial contractility, and diastolic function and decreased myocardial fibrosis after treatment. Concomitantly, numbers of capillaries and arterioles were increased. SWT resulted in enhanced expression of the chemoattractant stromal cell–derived factor 1 in ischemic myocardium and serum. Treatment induced recruitment of bone marrow–derived endothelial cells to the site of injury. In vitro, SWT resulted in endothelial cell proliferation, enhanced survival, and capillary sprouting. The effects were vascular endothelial growth factor receptor 2 and heparan sulfate proteoglycan dependent. Conclusions SWT positively affects heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis. SWT upregulated pivotal angiogenic and vasculogenic factors in the myocardium in vivo and induced proliferative and anti‐apoptotic effects on endothelial cells in vitro. Mechanistically, these effects depend on vascular endothelial growth factor signaling and heparan sulfate proteoglycans. SWT is a promising treatment option for regeneration of ischemic myocardium.
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Affiliation(s)
| | | | - Markus Theurl
- 3 Internal Medicine III Medical University of Innsbruck Austria
| | - Uwe Primessnig
- 4 Department of Internal Medicine and Cardiology Charité - Universitätsmedizin Berlin Germany
| | - Daniela Lener
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | - Elke Kirchmair
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | | | - Michael Graber
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | - Leo Pölzl
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | - Angela An
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | | | - Elisabeth Pechriggl
- 1 Division of Clinical and Functional Anatomy Department of Anatomy, Histology and Embryology Medical University of Innsbruck Austria
| | - Jakob Voelkl
- 4 Department of Internal Medicine and Cardiology Charité - Universitätsmedizin Berlin Germany
| | - Patrick Paulus
- 5 Department of Anaesthesiology and Operative Intensive Care Medicine Kepler University Hospital Linz Austria
| | - Wolfgang Schaden
- 6 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology AUVA Research Centre Vienna Austria.,7 Austrian Cluster for Tissue Regeneration Vienna Austria
| | - Michael Grimm
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | | | - Johannes Holfeld
- 2 Cardiac Surgery Medical University of Innsbruck Austria.,7 Austrian Cluster for Tissue Regeneration Vienna Austria
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31
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Facchin F, Canaider S, Tassinari R, Zannini C, Bianconi E, Taglioli V, Olivi E, Cavallini C, Tausel M, Ventura C. Physical energies to the rescue of damaged tissues. World J Stem Cells 2019; 11:297-321. [PMID: 31293714 PMCID: PMC6600852 DOI: 10.4252/wjsc.v11.i6.297] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 04/24/2019] [Accepted: 05/29/2019] [Indexed: 02/06/2023] Open
Abstract
Rhythmic oscillatory patterns sustain cellular dynamics, driving the concerted action of regulatory molecules, microtubules, and molecular motors. We describe cellular microtubules as oscillators capable of synchronization and swarming, generating mechanical and electric patterns that impact biomolecular recognition. We consider the biological relevance of seeing the inside of cells populated by a network of molecules that behave as bioelectronic circuits and chromophores. We discuss the novel perspectives disclosed by mechanobiology, bioelectromagnetism, and photobiomodulation, both in term of fundamental basic science and in light of the biomedical implication of using physical energies to govern (stem) cell fate. We focus on the feasibility of exploiting atomic force microscopy and hyperspectral imaging to detect signatures of nanomotions and electromagnetic radiation (light), respectively, generated by the stem cells across the specification of their multilineage repertoire. The chance is reported of using these signatures and the diffusive features of physical waves to direct specifically the differentiation program of stem cells in situ, where they already are resident in all the tissues of the human body. We discuss how this strategy may pave the way to a regenerative and precision medicine without the needs for (stem) cell or tissue transplantation. We describe a novel paradigm based upon boosting our inherent ability for self-healing.
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Affiliation(s)
- Federica Facchin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), School of Medicine, University of Bologna, Bologna 40100, Italy
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, CNR, Bologna 40100, Italy
| | - Silvia Canaider
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), School of Medicine, University of Bologna, Bologna 40100, Italy
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, CNR, Bologna 40100, Italy
| | - Riccardo Tassinari
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, CNR, Bologna 40100, Italy
| | - Chiara Zannini
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, CNR, Bologna 40100, Italy
| | - Eva Bianconi
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, CNR, Bologna 40100, Italy
| | - Valentina Taglioli
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, CNR, Bologna 40100, Italy
| | - Elena Olivi
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, CNR, Bologna 40100, Italy
| | - Claudia Cavallini
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, CNR, Bologna 40100, Italy
| | | | - Carlo Ventura
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), School of Medicine, University of Bologna, Bologna 40100, Italy
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, CNR, Bologna 40100, Italy.
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