Manipulating Cardiac Contractility in Heart Failure

Dorn, Gerald W.; Molkentin, Jeffery D.

doi:10.1161/01.cir.0000111581.15521.f5

Cited by 106 publications

(66 citation statements)

References 97 publications

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“…S17-S19). The intracellular tension and contractility of primary CMs also depend on these intra-and extrasarcomeric cytoskeletal structures (1,31,36,39). The expression levels of titin isoforms (N2A and N2B) and TnI and TnT differed in cultures of 7:1 hPSC-CMs on polyacrylamide vs. glass (SI Appendix, Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Disruption of the contractile activity of heart muscle cells, cardiomyocytes (CMs), can lead to heart disease, and altering CM contractility is a common approach to treating a failing heart (1). Single CMs contain all of the machinery involved in myocardial contractility (2), which consists of sarcomeres in series that shorten along myofibrils as a result of myosin activity (3).…”

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confidence: 99%

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Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Ribeiro

Ang

et al. 2015

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

413

456

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Single cardiomyocytes contain myofibrils that harbor the sarcomerebased contractile machinery of the myocardium. Cardiomyocytes differentiated from human pluripotent stem cells (hPSC-CMs) have potential as an in vitro model of heart activity. However, their fetallike misalignment of myofibrils limits their usefulness for modeling contractile activity. We analyzed the effects of cell shape and substrate stiffness on the shortening and movement of labeled sarcomeres and the translation of sarcomere activity to mechanical output (contractility) in live engineered hPSC-CMs. Single hPSC-CMs were cultured on polyacrylamide substrates of physiological stiffness (10 kPa), and Matrigel micropatterns were used to generate physiological shapes (2,000-μm 2 rectangles with length:width aspect ratios of 5:1-7:1) and a mature alignment of myofibrils. Translation of sarcomere shortening to mechanical output was highest in 7:1 hPSC-CMs. Increased substrate stiffness and applied overstretch induced myofibril defects in 7:1 hPSC-CMs and decreased mechanical output. Inhibitors of nonmuscle myosin activity repressed the assembly of myofibrils, showing that subcellular tension drives the improved contractile activity in these engineered hPSC-CMs. Other factors associated with improved contractility were axially directed calcium flow, systematic mitochondrial distribution, more mature electrophysiology, and evidence of transverse-tubule formation. These findings support the potential of these engineered hPSC-CMs as powerful models for studying myocardial contractility at the cellular level.contractility | sarcomeres | cardiomyocyte | stem cell | single cell

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Ribeiro

Ang

et al. 2015

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

413

456

View full text Add to dashboard Cite

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“…Accordingly, drugs intended to reverse or bypass β-adrenergic desensitization (PDE inhibitors, catecholamines, or other positive inotropic agents) caused symptomatic improvement but increased mortality in patients. Similarly, except for expression of adenylyl cyclase 6 and inhibitors of the G protein-coupled receptor kinase 2, transgenic overexpression of proximal elements of the β-adrenergic signaling pathway (receptors, G proteins, adenylyl cyclase 5, or PKA) caused short-term improvements in cardiac function but long-term cardiac pathology (2,7). In contrast, transgenic or viral overexpression of SERCA2a, an important downstream target of β-adrenergic regulation of cardiac function (via phosphorylation of phospholamban [PLB]), improved diastolic and systolic function and the energetic state of failing hearts (8).…”

Section: Introductionmentioning

confidence: 99%

Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging

Wittköpper

Fabritz²,

Neef³

et al. 2010

J. Clin. Invest.

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Phosphatase inhibitor-1 (I-1) is a distal amplifier element of β-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyterestricted expression of I-1c (referred to herein as dTG I-1c mice) on an I-1-deficient background. Young adult dTG I-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyterestricted I-1c and reversed all abnormalities. Hearts from dTG I-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca 2+ sparks in isolated myocytes. Aged dTG I-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-α (I-1 S67A ). In conclusion, conditional expression of I-1c or I-1 S67A enhanced steady-state phosphorylation of 2 key Ca 2+ -regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure. IntroductionHeart failure is among the most frequent causes of morbidity and mortality worldwide and is, despite improved treatment options, associated with poor prognosis. Current treatment with angiotensin-converting enzyme inhibitors, aldosterone receptor antagonists, and beta blockers is suboptimal, with the 5-year survival rate being less than 50%. New drug principles targeting neurohumoral activation mechanisms, such as antagonists of endothelin receptors, TNF-α or IL-6, and statins, failed to improve survival in clinical studies. Thus, new approaches are needed, and an attractive one is to target the abnormal function of cardiomyocytes in failing hearts directly (as opposed to the more indirect affection by neurohumoral blockade).Two of the best studied alterations of failing myocyte function are (a) desensitization of the β-adrenergic signaling system (1, 2) and (b) alterations of intracellular Ca 2+ handling (3, 4). The latter include decreased diastolic sarcoplasmic reticulum (SR) Ca 2+ uptake via the SR Ca 2+ ATPase (SERCA2a) and relatively increased

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“…9,10 Especially useful for directing cardiac overexpression has been the murine ␣-myosin heavy chain (MHC) promoter, which reproducibly provides high-level cardiomyocyte-specific transgene expression in a copy numberdependent and position-independent manner. 9 -11 This transgenic system has been used in more than 150 published cardiac-specific overexpression models, many of which have helped to establish critical roles for the expressed transgene based on the development of striking heart phenotypes.…”

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confidence: 99%

“…9 -11 This transgenic system has been used in more than 150 published cardiac-specific overexpression models, many of which have helped to establish critical roles for the expressed transgene based on the development of striking heart phenotypes. 9,10 Because it is largely silent in the ventricles until birth and then expresses robustly, 11 ␣-MHC-directed expression of toxic genes is not lethal during embryogenesis, but causes early lethality [12][13][14] or phenotypic progression during early life. 13,15 The characteristic temporal pattern of conventional ␣-MHC-directed transgene expression, with atrial expression before and after birth and ventricular induction at approximately the time of birth, results in robust transgene expression and accumulation of transgenic protein during a period of rapid heart growth.…”

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confidence: 99%

Physiological Growth Synergizes With Pathological Genes in Experimental Cardiomyopathy

Syed

Odley

Hahn

et al. 2004

Circulation Research

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Abstract-Hundreds of signaling molecules have been assigned critical roles in the pathogenesis of myocardial hypertrophy and heart failure based on cardiac phenotypes from ␣-myosin heavy chain-directed overexpression mice. Because permanent ventricular transgene expression in this system begins during a period of rapid physiological neonatal growth, resulting phenotypes are the combined consequences of transgene effects and normal trophic influences. We used temporally-defined forced gene expression to investigate synergy between postnatal physiological cardiac growth and two functionally divergent cardiomyopathic genes.

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Manipulating Cardiac Contractility in Heart Failure

Cited by 106 publications

References 97 publications

Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging

Physiological Growth Synergizes With Pathological Genes in Experimental Cardiomyopathy

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