|
1
|
Liu C, Chen Y, Xie Y, Xiang M. Tubulin Post-translational Modifications: Potential Therapeutic Approaches to Heart Failure. Front Cell Dev Biol 2022; 10:872058. [PMID: 35493101 PMCID: PMC9039000 DOI: 10.3389/fcell.2022.872058] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/09/2022] [Indexed: 11/13/2022] Open
Abstract
In recent decades, advancing insights into the mechanisms of cardiac dysfunction have focused on the involvement of microtubule network. A variety of tubulin post-translational modifications have been discovered to fine-tune the microtubules’ properties and functions. Given the limits of therapies based on conserved structures of the skeleton, targeting tubulin modifications appears to be a potentially promising therapeutic strategy. Here we review the current understanding of tubulin post-translational modifications in regulating microtubule functions in the cardiac system. We also discussed how altered modifications may lead to a range of cardiac dysfunctions, many of which are linked to heart failure.
Collapse
Affiliation(s)
- Chang Liu
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuwen Chen
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yao Xie
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Meixiang Xiang
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
2
|
Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure. Nat Commun 2019; 10:5754. [PMID: 31848331 PMCID: PMC6917736 DOI: 10.1038/s41467-019-13623-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 11/11/2019] [Indexed: 01/06/2023] Open
Abstract
Heart failure is the major cause of death for muscular dystrophy patients, however, the molecular pathomechanism remains unknown. Here, we show the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced α-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi-microtubule networks, which were ameliorated with colchicine treatment. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and thus, the results may lead to strategies for therapeutic intervention. Mutations in Ftkn cause Fukuyama muscular dystrophy, and heart failure is the main cause of death in thes patients. Here the authors show that acute elimination of Fktn in adult mice causes early mortality, and this is associated with myocyte dysfunction, with disorganised Golg-microtubule networks, and that the pathology can be ameliorated with colchicine treatment.
Collapse
|
|
3
|
Grimes KM, Prasad V, McNamara JW. Supporting the heart: Functions of the cardiomyocyte's non-sarcomeric cytoskeleton. J Mol Cell Cardiol 2019; 131:187-196. [PMID: 30978342 DOI: 10.1016/j.yjmcc.2019.04.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 04/02/2019] [Accepted: 04/05/2019] [Indexed: 02/06/2023]
Abstract
The non-contractile cytoskeleton in cardiomyocytes is comprised of cytoplasmic actin, microtubules, and intermediate filaments. In addition to providing mechanical support to these cells, these structures are important effectors of tension-sensing and signal transduction and also provide networks for the transport of proteins and organelles. The majority of our knowledge on the function and structure of these cytoskeletal networks comes from research on proliferative cell types. However, in recent years, researchers have begun to show that there are important cardiomyocyte-specific functions of the cytoskeleton. Here we will discuss the current state of cytoskeletal biology in cardiomyocytes, as well as research from other cell types, that together suggest there is a wealth of knowledge on cardiac health and disease waiting to be uncovered through exploration of the complex signaling networks of cardiomyocyte non-sarcomeric cytoskeletal proteins.
Collapse
Affiliation(s)
- Kelly M Grimes
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
| | - Vikram Prasad
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - James W McNamara
- Heart, Lung and Vascular Institute, University of Cincinnati, Cincinnati, OH, USA
| |
Collapse
|
|
4
|
Quintana MT, He J, Sullivan J, Grevengoed T, Schisler J, Han Y, Hill JA, Yates CC, Stansfield WE, Mapanga RF, Essop MF, Muehlbauer MJ, Newgard CB, Bain JR, Willis MS. Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet. BMC Endocr Disord 2015; 15:36. [PMID: 26215257 PMCID: PMC4515942 DOI: 10.1186/s12902-015-0028-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The pathogenesis of diabetic cardiomyopathy (DCM) involves the enhanced activation of peroxisome proliferator activating receptor (PPAR) transcription factors, including the most prominent isoform in the heart, PPARα. In cancer cells and adipocytes, post-translational modification of PPARs have been identified, including ligand-dependent degradation of PPARs by specific ubiquitin ligases. However, the regulation of PPARs in cardiomyocytes and heart have not previously been identified. We recently identified that muscle ring finger-1 (MuRF1) and MuRF2 differentially inhibit PPAR activities by mono-ubiquitination, leading to the hypothesis that MuRF3 may regulate PPAR activity in vivo to regulate DCM. METHODS MuRF3-/- mice were challenged with 26 weeks 60% high fat diet to induce insulin resistance and DCM. Conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARβ, and PPARγ1 activities were assayed. RESULTS MuRF3-/- mice exhibited a premature systolic heart failure by 6 weeks high fat diet (vs. 12 weeks in MuRF3+/+). MuRF3-/- mice weighed significantly less than sibling-matched wildtype mice after 26 weeks HFD. These differences may be largely due to resistance to fat accumulation, as MRI analysis revealed MuRF3-/- mice had significantly less fat mass, but not lean body mass. In vitro ubiquitination assays identified MuRF3 mono-ubiquitinated PPARα and PPARγ1, but not PPARβ. CONCLUSIONS These findings suggest that MuRF3 helps stabilize cardiac PPARα and PPARγ1 in vivo to support resistance to the development of DCM. MuRF3 also plays an unexpected role in regulating fat storage despite being found only in striated muscle.
Collapse
Affiliation(s)
- Megan T Quintana
- Department of Surgery, University of North Carolina, Chapel Hill, NC, USA.
| | - Jun He
- Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
- General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China.
| | - Jenyth Sullivan
- Department of Biology, University of North Carolina, Chapel Hill, NC, USA.
| | - Trisha Grevengoed
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
| | - Jonathan Schisler
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
- Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
| | - Yipin Han
- North Carolina State University, Department of Engineering, Raleigh, NC, USA.
| | - Joseph A Hill
- Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Cecelia C Yates
- Department of Health Promotions and Development, School of Nursing, University of Pittsburgh, Pittsburgh, PA, USA.
| | | | - Rudo F Mapanga
- Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa.
| | - M Faadiel Essop
- Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa.
| | - Michael J Muehlbauer
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
| | - Christopher B Newgard
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
| | - James R Bain
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
| | - Monte S Willis
- Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
| |
Collapse
|
|
5
|
Waddingham MT, Edgley AJ, Tsuchimochi H, Kelly DJ, Shirai M, Pearson JT. Contractile apparatus dysfunction early in the pathophysiology of diabetic cardiomyopathy. World J Diabetes 2015; 6:943-960. [PMID: 26185602 PMCID: PMC4499528 DOI: 10.4239/wjd.v6.i7.943] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 12/30/2014] [Accepted: 03/09/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients. Independent of hypertension and coronary artery disease, diabetes is associated with a specific cardiomyopathy, known as diabetic cardiomyopathy (DCM). Four decades of research in experimental animal models and advances in clinical imaging techniques suggest that DCM is a progressive disease, beginning early after the onset of type 1 and type 2 diabetes, ahead of left ventricular remodeling and overt diastolic dysfunction. Although the molecular pathogenesis of early DCM still remains largely unclear, activation of protein kinase C appears to be central in driving the oxidative stress dependent and independent pathways in the development of contractile dysfunction. Multiple subcellular alterations to the cardiomyocyte are now being highlighted as critical events in the early changes to the rate of force development, relaxation and stability under pathophysiological stresses. These changes include perturbed calcium handling, suppressed activity of aerobic energy producing enzymes, altered transcriptional and posttranslational modification of membrane and sarcomeric cytoskeletal proteins, reduced actin-myosin cross-bridge cycling and dynamics, and changed myofilament calcium sensitivity. In this review, we will present and discuss novel aspects of the molecular pathogenesis of early DCM, with a special focus on the sarcomeric contractile apparatus.
Collapse
|
|
6
|
Goyal BR, Mehta AA. Diabetic cardiomyopathy: pathophysiological mechanisms and cardiac dysfuntion. Hum Exp Toxicol 2012; 32:571-90. [PMID: 23174745 DOI: 10.1177/0960327112450885] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Several experimental, pathological, epidemiological, and clinical studies have clearly depicted that diabetes mellitus results in cardiac functional and structural changes. Diabetic cardiomyopathy results in both structural and functional alterations in the myocardium. Several mechanisms have been implicated in the pathophysiology of diabetic cardiomyopathy. Of these, metabolic disturbances, myocardial fibrosis, small vessel disease, and cardiac autonomic neuropathy are the major players in the pathophysiology of diabetic cardiomyopathy. This review is intended to discuss various such pathophysiological mechanisms of diabetic cardiomyopathy. We have also described the systolic and diastolic dysfunctioning and its corelation to structural changes in diabetes.
Collapse
Affiliation(s)
- B R Goyal
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
| | | |
Collapse
|
|
7
|
Watanabe K, Thandavarayan RA, Harima M, Sari FR, Gurusamy N, Veeraveedu PT, Mito S, Arozal W, Sukumaran V, Laksmanan AP, Soetikno V, Kodama M, Aizawa Y. Role of differential signaling pathways and oxidative stress in diabetic cardiomyopathy. Curr Cardiol Rev 2011; 6:280-90. [PMID: 22043204 PMCID: PMC3083809 DOI: 10.2174/157340310793566145] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Revised: 09/03/2010] [Accepted: 09/15/2010] [Indexed: 12/20/2022] Open
Abstract
Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Hyperglycemia-induced oxidative stress is a major risk factor for the development of micro-vascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis and endothelial dysfunction. Diabetes-mediated biochemical changes show cross-interaction and complex interplay culminating in the activation of several intracellular signaling molecules. Diabetic cardiomyopathy is characterized by morphologic and structural changes in the myocardium and coronary vasculature mediated by the activation of various signaling pathways. This review focuses on the oxidative stress and signaling pathways in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic cardiomyopathy.
Collapse
Affiliation(s)
- Kenichi Watanabe
- Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata City, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Howarth FC, Almugaddum FA, Qureshi MA, Ljubisavljevic M. The effects of heavy long-term exercise on ventricular myocyte shortening and intracellular Ca2+ in streptozotocin-induced diabetic rat. J Diabetes Complications 2010; 24:278-85. [PMID: 19395278 DOI: 10.1016/j.jdiacomp.2009.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2008] [Revised: 02/09/2009] [Accepted: 03/11/2009] [Indexed: 11/24/2022]
Abstract
OBJECTIVE This study investigated whether exercise training, initiated at the onset of diabetes, could preserve the contractile properties of ventricular myocytes. RESEARCH DESIGN AND METHODS The effects of a heavy exercise training program on shortening and intracellular Ca(2+) in unloaded ventricular myocytes from streptozotocin (STZ)-induced diabetic rats were examined. Animals were divided into four groups: control sedentary (CS), diabetic sedentary (DS), control heavy exercise (CHE), and diabetic heavy exercise (DHE). Exercise protocol: 5x60 min/week, 18 m/min, 5% gradient. Exercise training began 1 week after STZ treatment and continued for 12-23 (mean 17.5) weeks. RESULTS Diabetes induced prolongation of time-to-peak (TPK) shortening (124+/-2 ms in DS compared to 97+/-2 ms in CS rats), which was further increased by exercise (133+/-3 ms in DHE and 112+/-2 ms in CHE myocytes). Diabetes had no significant effects on time-to-half (THALF) relaxation of shortening (61+/-2 ms in DS compared to 56+/-2 ms in CS myocytes). Exercise induced significant prolongation of THALF in control (66+/-3 ms) but not in diabetic (69+/-3 ms) myocytes. Diabetes, though not exercise, significantly prolonged TPK (76+/-3 ms in DS compared to 64+/-2 ms in CS) and THALF recovery (160+/-5 ms in DS compared to 118+/-4 ms in CS) of the Ca(2+) transient. Neither diabetes nor exercise had significant effects on the amplitude of myocyte shortening and the Ca(2+) transient. CONCLUSIONS Heavy long-term exercise alters the dynamics but not the amplitude of unloaded myocyte contraction in the STZ-induced diabetic rat.
Collapse
MESH Headings
- Animals
- Calcium/metabolism
- Cell Size
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Experimental/physiopathology
- Heart Ventricles/metabolism
- Heart Ventricles/pathology
- Heart Ventricles/physiopathology
- Intracellular Space/metabolism
- Male
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Myocytes, Cardiac/physiology
- Physical Conditioning, Animal/adverse effects
- Physical Conditioning, Animal/physiology
- Physical Exertion/physiology
- Rats
- Rats, Wistar
- Streptozocin
- Time Factors
Collapse
Affiliation(s)
- Frank Christopher Howarth
- Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE.
| | | | | | | |
Collapse
|
|
9
|
Hu JY, Chu ZG, Han J, Dang YM, Yan H, Zhang Q, Liang GP, Huang YS. The p38/MAPK pathway regulates microtubule polymerization through phosphorylation of MAP4 and Op18 in hypoxic cells. Cell Mol Life Sci 2010; 67:321-33. [PMID: 19915797 PMCID: PMC11115776 DOI: 10.1007/s00018-009-0187-z] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Revised: 10/13/2009] [Accepted: 10/16/2009] [Indexed: 02/07/2023]
Abstract
In both cardiomyocytes and HeLa cells, hypoxia (1% O(2)) quickly leads to microtubule disruption, but little is known about how microtubule dynamics change during the early stages of hypoxia. We demonstrate that microtubule associated protein 4 (MAP4) phosphorylation increases while oncoprotein 18/stathmin (Op18) phosphorylation decreases after hypoxia, but their protein levels do not change. p38/MAPK activity increases quickly after hypoxia concomitant with MAP4 phosphorylation, and the activated p38/MAPK signaling leads to MAP4 phosphorylation and to Op18 dephosphorylation, both of which induce microtubule disruption. We confirmed the interaction between phospho-p38 and MAP4 using immunoprecipitation and found that SB203580, a p38/MAPK inhibitor, increases and MKK6(Glu) overexpression decreases hypoxic cell viability. Our results demonstrate that hypoxia induces microtubule depolymerization and decreased cell viability via the activation of the p38/MAPK signaling pathway and changes the phosphorylation levels of its downstream effectors, MAP4 and Op18.
Collapse
Affiliation(s)
- Jiong-Yu Hu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, 400038 Chongqing, People’s Republic of China
| | - Zhi-Gang Chu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, 400038 Chongqing, People’s Republic of China
| | - Jian Han
- Department of Gynecology and Obstetrics, Daping Hospital, The Third Military Medical University, 400038 Chongqing, People’s Republic of China
| | - Yong-ming Dang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, 400038 Chongqing, People’s Republic of China
| | - Hong Yan
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, 400038 Chongqing, People’s Republic of China
| | - Qiong Zhang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, 400038 Chongqing, People’s Republic of China
| | - Guang-ping Liang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, 400038 Chongqing, People’s Republic of China
| | - Yue-Sheng Huang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, 400038 Chongqing, People’s Republic of China
| |
Collapse
|
|
10
|
|
|
11
|
Cheng G, Zile MR, Takahashi M, Baicu CF, Bonnema DD, Cabral F, Menick DR, Cooper G. A direct test of the hypothesis that increased microtubule network density contributes to contractile dysfunction of the hypertrophied heart. Am J Physiol Heart Circ Physiol 2008; 294:H2231-41. [DOI: 10.1152/ajpheart.91515.2007] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Contractile dysfunction in pressure overload-hypertrophied myocardium has been attributed in part to the increased density of a stabilized cardiocyte microtubule network. The present study, the first to employ wild-type and mutant tubulin transgenes in a living animal, directly addresses this microtubule hypothesis by defining the contractile mechanics of the normal and hypertrophied left ventricle (LV) and its constituent cardiocytes from transgenic mice having cardiac-restricted replacement of native β4-tubulin with β1-tubulin mutants that had been selected for their effects on microtubule stability and thus microtubule network density. In each case, the replacement of cardiac β4-tubulin with mutant hemagglutinin-tagged β1-tubulin was well tolerated in vivo. When LVs in intact mice and cardiocytes from these same LVs were examined in terms of contractile mechanics, baseline function was reduced in mice with genetically hyperstabilized microtubules, and hypertrophy-related contractile dysfunction was exacerbated. However, in mice with genetically hypostabilized cardiac microtubules, hypertrophy-related contractile dysfunction was ameliorated. Thus, in direct support of the microtubule hypothesis, we show here that cardiocyte microtubule network density, as an isolated variable, is inversely related to contractile function in vivo and in vitro, and microtubule instability rescues most of the contractile dysfunction seen in pressure overload-hypertrophied myocardium.
Collapse
|
|
12
|
Shiels H, O'Connell A, Qureshi MA, Howarth FC, White E, Calaghan S. Stable microtubules contribute to cardiac dysfunction in the streptozotocin-induced model of type 1 diabetes in the rat. Mol Cell Biochem 2006; 294:173-80. [PMID: 16838107 DOI: 10.1007/s11010-006-9257-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2006] [Accepted: 06/01/2006] [Indexed: 02/06/2023]
Abstract
Cardiac microtubule stability is increased in the streptozotocin (STZ) model of type 1 diabetes. Here, we investigate the reason for increased microtubule stability, and the functional consequences of stable microtubule disruption. Ventricular myocytes were isolated from rats at 8-12 weeks after injection of STZ. A 10% increase in microtubule density, but no difference in the ratio of microtubule-associated protein 4 (MAP4) to tubulin was seen in myocytes from STZ rats. Functionally, STZ myocytes showed a tendency for reduced shortening and intracellular Ca2+ ([Ca2+]i) transient amplitude, and a significant prolongation of time to peak (ttp) shortening and [Ca2+]i. Although microtubules in STZ myocytes were less sensitive to the microtubule disruptor nocodazole (NOC; 33 microM) than control myocytes, we only saw marked functional consequences of microtubule disruption by NOC in myocytes from diabetic animals. NOC increased shortening and [Ca2+]i transient amplitude in STZ myocytes by 45 and 24%, respectively (compared with 4 and 6% in controls). Likewise, NOC decreased ttp shortening and [Ca2+]i only in STZ myocytes, such that these parameters were no longer different between the two groups. In conclusion, stable microtubules in diabetes are not associated with an increase in MAP4, but are functionally relevant to cardiac dysfunction in diabetes, regulating both [Ca2+]i and shortening.
Collapse
Affiliation(s)
- Holly Shiels
- Faculty of Life Sciences, Core Technology Facility, University of Manchester, 46 Grafton St, Manchester , M13 9PT, UK
| | | | | | | | | | | |
Collapse
|
|
13
|
Abstract
The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial. This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications. The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes. The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity). This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.
Collapse
Affiliation(s)
- Zhi You Fang
- University of Queensland, Brisbane, 4012, Australia
| | | | | |
Collapse
|
|
14
|
Calaghan SC, Le Guennec JY, White E. Cytoskeletal modulation of electrical and mechanical activity in cardiac myocytes. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2004; 84:29-59. [PMID: 14642867 DOI: 10.1016/s0079-6107(03)00057-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The cardiac myocyte has an intracellular scaffold, the cytoskeleton, which has been implicated in several cardiac pathologies including hypertrophy and failure. In this review we describe the role that the cytoskeleton plays in modulating both the electrical activity (through ion channels and exchangers) and mechanical (or contractile) activity of the adult heart. We focus on the 3 components of the cytoskeleton, actin microfilaments, microtubules, and desmin filaments. The limited visual data available suggest that the subsarcolemmal actin cytoskeleton is sparse in the adult myocyte. Selective disruption of cytoskeletal actin by pharmacological tools has yet to be verified in the adult cell, yet evidence exists for modulation of several ionic currents, including I(CaL), I(Na), I(KATP), I(SAC) by actin microfilaments. Microtubules exist as a dense network throughout the adult cardiac cell, and their structure, architecture, kinetics and pharmacological manipulation are well described. Both polymerised and free tubulin are functionally significant. Microtubule proliferation reduces contraction by impeding sarcomeric motion; modulation of sarcoplasmic reticulum Ca(2+) release may also be involved in this effect. The lack of effect of microtubule disruption on cardiac contractility in adult myocytes, and the concentration-dependent modulation of the rate of contraction by the disruptor nocodazole in neonatal myocytes, support the existence of functionally distinct microtubule populations. We address the controversy regarding the stimulation of the beta-adrenergic signalling pathway by free tubulin. Work with mice lacking desmin has demonstrated the importance of intermediate filaments to normal cardiac function, but the precise role that desmin plays in the electrical and mechanical activity of cardiac muscle has yet to be determined.
Collapse
Affiliation(s)
- S C Calaghan
- School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK
| | | | | |
Collapse
|
|
15
|
Brette F, Komukai K, Orchard CH. Validation of formamide as a detubulation agent in isolated rat cardiac cells. Am J Physiol Heart Circ Physiol 2002; 283:H1720-8. [PMID: 12234828 DOI: 10.1152/ajpheart.00347.2002] [Citation(s) in RCA: 90] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Kawai M, Hussain M, and Orchard CH. Am J Heart Circ Physiol 277: H603-H609, 1999 developed a technique to detubulate rat ventricular myocytes using formamide and showed that detubulation results in a decrease in cell capacitance, Ca(2+) current density, and Ca(2+) transient amplitude. We have investigated the mechanism of this detubulation and possible direct effects of formamide. Staining ventricular cells with di-8-ANEPPS showed that the t tubule membranes remain inside the cell after detubulation; trapping of FITC-labeled dextran within the t tubules showed that detubulation occurs during formamide washout and that the t tubules appear to reseal within the cell. Detubulation had no effect on the microtubule network but resulted in loss of synchronous Ca(2+) release on electrical stimulation. In contrast, formamide treatment of atrial cells did not significantly change cell capacitance, Ca(2+) current amplitude, action potential configuration, the Ca(2+) transient or the response of the Ca(2+) transient to isoprenaline. We conclude that formamide washout induces detubulation of single rat ventricular myocytes, leaving the t tubules within the cell, but without direct effects on cell proteins that might alter cell function.
Collapse
Affiliation(s)
- Fabien Brette
- School of Biomedical Sciences, University of Leeds, United Kingdom
| | | | | |
Collapse
|