Stretch-induced hypertrophy of isolated adult rabbit cardiomyocytes

Blaauw, Erik; Nieuwenhoven, Frans A. van; Willemsen, P. H. M.; Delhaas, Tammo; Prinzen, Frits W.; Snoeckx, L. H. E. H.; Bilsen, Marc van; Vusse, Ger J.

doi:10.1152/ajpheart.00822.2009

Cited by 36 publications

(37 citation statements)

References 54 publications

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“…By contrast, SRF and NFATc4 (both known target genes of miR‐133a) did not show any relation with miR‐133a in this study and are most likely not involved in the hypertrophic response in our model of local hypertrophy. In vitro studies showed that increased CTGF expression in isolated, stretched cardiomyocytes coincided with development of a hypertrophic response 1, 3. Moreover, in a rabbit model of eccentric hypertrophy, where strains and workload are expected to be high throughout the LV wall, CTGF was also found to be overexpressed 3.…”

Section: Discussionmentioning

confidence: 97%

“…However, in vivo , it is difficult to separate the contribution of (local) mechanical load and (systemic) neurohumoral activation, because global cardiac overload, as in hypertension and valvular disease, also leads to neurohumoral stimulation/activation. On the other hand, it has been shown that stretching isolated cardiomyocytes can affect gene expression, increase protein synthesis, and induce hypertrophy 1. Similarly, stretching isolated cardiac fibroblasts increases expression of extracellular matrix (ECM) genes and proteins 2, 3…”

Section: Introductionmentioning

confidence: 99%

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Local microRNA‐133a downregulation is associated with hypertrophy in the dyssynchronous heart

et al. 2017

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AimsLeft bundle branch block (LBBB) creates considerable regional differences in mechanical load within the left ventricle (LV). We investigated expression of selected microRNAs (miRs) in relation to regional hypertrophy and fibrosis in LBBB hearts and their reversibility upon cardiac resynchronization therapy (CRT).Methods and resultsEighteen dogs were followed for 4 months after induction of LBBB, 10 of which received CRT after 2 months. Five additional dogs served as control. LV geometric changes were determined by echocardiography and myocardial strain by magnetic resonance imaging tagging. Expression levels of miRs, their target genes: connective tissue growth factor (CTGF), serum response factor (SRF), nuclear factor of activated T cells (NFATc4), and cardiomyocyte diameter and collagen deposition were measured in the septum and LV free wall (LVfw). In LBBB hearts, LVfw and septal systolic circumferential strain were 200% and 50% of control, respectively. This coincided with local hypertrophy in the LVfw. MiR‐133a expression was reduced by 33% in the LVfw, which corresponded with a selective increase of CTGF expression in the LVfw (279% of control). By contrast, no change was observed in SRF and NFATc4 expression was decreased in LBBB hearts. CRT normalized strain patterns and reversed miR‐133a and CTGF expression towards normal, expression of other miRs, related to remodelling, such as miR‐199b and miR‐155f, were not affected.ConclusionsIn the clinically relevant large animal model of LBBB, a close inverse relation exists between local hypertrophy and miR‐133a. Reduced miR‐133a correlated with increased CTGF levels but not with SRF and NFATc4.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Local microRNA‐133a downregulation is associated with hypertrophy in the dyssynchronous heart

et al. 2017

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“…In response to cyclic mechanical strain, cardiac myocytes in vitro become hypertrophic, as signified by increases in cell size and overall protein expression [19,32,46,158] and the activation of fetal gene programs [63]. Therefore, cyclic stretch is an extrinsic cue that induces intrinsic changes in gene expression, presumably to equip the myocyte to better cope with the mechanical load.…”

Section: Gene Expressionmentioning

confidence: 99%

Mechanotransduction: the role of mechanical stress, myocyte shape, and cytoskeletal architecture on cardiac function

McCain

Parker

2011

Pflugers Arch - Eur J Physiol

192

178

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Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease, requiring cardiac myocytes to be mechanically durable and capable of fusing a variety of environmental signals on different time scales. During physiological growth, myocytes adaptively remodel to mechanical loads. Pathological stimuli can induce maladaptive remodeling. In both of these conditions, the cytoskeleton plays a pivotal role in both sensing mechanical stress and mediating structural remodeling and functional responses within the myocyte.

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“…For example, cardiac hypertrophy and heart failure are reproduced in the rat by ligating coronary arteries or by using the spontaneously hypertensive rat strain (15). In vitro, heart disease has been modeled by exposing primary cardiac myocytes to chemical (16) or exogenous mechanical stimuli (17)(18)(19)(20)(21), which increases cell size, activates pathological gene expression, and remodels ion channel currents. However, cell culture systems often fail to predict the efficacy or toxicity of therapeutic candidates, potentially because they do not replicate the complex structurefunction relationships of native cardiac tissue (22).…”

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confidence: 99%

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

McCain

Sheehy

Grosberg

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

136

124

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The lack of a robust pipeline of medical therapeutic agents for the treatment of heart disease may be partially attributed to the lack of in vitro models that recapitulate the essential structurefunction relationships of healthy and diseased myocardium. We designed and built a system to mimic mechanical overload in vitro by applying cyclic stretch to engineered laminar ventricular tissue on a stretchable chip. To test our model, we quantified changes in gene expression, myocyte architecture, calcium handling, and contractile function and compared our results vs. several decades of animal studies and clinical observations. Cyclic stretch activated gene expression profiles characteristic of pathological remodeling, including decreased α-to β-myosin heavy chain ratios, and induced maladaptive changes to myocyte shape and sarcomere alignment. In stretched tissues, calcium transients resembled those reported in failing myocytes and peak systolic stress was significantly reduced. Our results suggest that failing myocardium, as defined genetically, structurally, and functionally, can be replicated in an in vitro microsystem by faithfully recapitulating the structural and mechanical microenvironment of the diseased heart. organs on chips | mechanotransduction | muscular thin films | microarray | contraction

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Stretch-induced hypertrophy of isolated adult rabbit cardiomyocytes

Abstract: Blaauw E, van Nieuwenhoven FA, Willemsen P, Delhaas T, Prinzen FW, Snoeckx LH, van Bilsen M, van der Vusse GJ. Stretch-induced hypertrophy of isolated adult rabbit cardiomyocytes.

Cited by 36 publications

References 54 publications

Local microRNA‐133a downregulation is associated with hypertrophy in the dyssynchronous heart

Local microRNA‐133a downregulation is associated with hypertrophy in the dyssynchronous heart

Mechanotransduction: the role of mechanical stress, myocyte shape, and cytoskeletal architecture on cardiac function

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

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