The Rho kinase inhibitor, fasudil, ameliorates diabetes-induced cardiac dysfunction by improving calcium clearance and actin remodeling

Lai, Dongwu; Gao, Jing; Bi, Xiwen; He, Hong; Shi, Xiaolu; Weng, Shaoxiang; Chen, Yu; Yang, Ying; Yue, Yang; Fu, Guosheng

doi:10.1007/s00109-016-1469-1

Cited by 32 publications

(24 citation statements)

References 42 publications

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“…Importantly, ROCK inhibition did not negatively interfere with the contractile function of the EHM, but showed by trend a slight improvement. Due to the unchanged calcium sensitivity, we believe that this improvement is more likely based on a better diastolic compliance of the tissues than on molecular changes in the excitation-contraction coupling in cardiomyocytes, which was described to be a potential consequence of ROCK inhibition [53,54]. Similar as found in ECT, ROCK inhibition did not affect tissue extensibility.…”

Section: Discussionmentioning

confidence: 56%

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos

Hartmann

Zimmermann

et al. 2019

Journal of Molecular and Cellular Cardiology

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Cardiac fibrosis is a hallmark of heart failure for which there is no effective pharmacological therapy. By genetic modification and in vivo inhibitor approaches it was suggested that the Rho-associated kinases (ROCK1 and ROCK2) are involved in pro-fibrotic signalling in cardiac fibroblasts and that they may serve as targets for anti-fibrotic therapies. We demonstrate that simultaneous inhibition of ROCK1 and ROCK2 strongly interfered with tissue formation and their biomechanical properties in a model of engineered connective tissue (ECT), comprised of cardiac fibroblasts and collagen. These effects were observed with both rat and human ECT. Inhibitors of different chemistries, including the isoquinoline inhibitors Fasudil and H1152P as well as the pyrazol-phenyl inhibitor SR-3677, showed comparable effects. By combined treatment of ECT with TGF-β and H1152P, we could identify ROCK as a mediator of TGF-β-dependent tissue stiffening. Moreover, expression analyses suggested that lysyl oxidase (LOX) is a downstream target of the ROCK-actin-MRTF/SRF pathway and inhibition of this pathway by Latrunculin A and CCG-203971 showed similar anti-fibrotic effects in the ECT model as ROCK inhibitors. In line with the collagen crosslinking function of LOX, its inhibition by βaminopropionitrile resulted in reduced ECT stiffness, but let tissue compaction unaffected. Finally, we show that ROCK inhibition also reduced the compaction and stiffness of engineered heart muscle tissues. Our results indicate that pharmacological inhibition of ROCK has a strong anti-fibrotic potential which is in part due to a decrease in the expression of the collagen crosslinking enzyme lysyl oxidase.

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Section: Discussionmentioning

confidence: 56%

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos

Hartmann

Zimmermann

et al. 2019

Journal of Molecular and Cellular Cardiology

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“…Recently, Gao et al found that fasudil suppresses HG‐induced H9c2 cell early apoptosis through activation of autophagy . Lai et al show that fasudil ameliorates diabetes‐induced cardiac dysfunction by improving calcium clearance and actin remodelling . These studies collectively indicate that inhibition of ROCK in the HG state protects against cardiomyocyte apoptosis through different molecular mechanisms.…”

Section: Discussionmentioning

confidence: 97%

The RhoA/ROCK pathway mediates high glucose‐induced cardiomyocyte apoptosis via oxidative stress, JNK, and p38MAPK pathways

Zhou

Sun

Zhang

et al. 2018

Diabetes Metabolism Res

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“…Adult rat cardiomyocytes were isolated as previously described [13]. Four hours after an LPS injection, the hearts were isolated from LPS-treated rats, washed, and retroperfused through the aorta using a Langendorff apparatus.…”

Section: Methodsmentioning

confidence: 99%

The Trend of β<sub>3</sub>-Adrenergic Receptor in the Development of Septic Myocardial Depression: A Lipopolysaccharide-Induced Rat Septic Shock Model

et al. 2018

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Septic shock with low cardiac output is very common in children. However, the mechanism underlying myocardial depression is unclear. The role of β₃-AR in the development of myocardial depression in sepsis is unknown. In the present study, we generated an adolescent rat model of hypodynamic septic shock induced by lipopolysaccharide (LPS). Neonatal cardiomyocytes were also treated with LPS to mimic myocardial depression in sepsis, which was confirmed via an in vivo left ventricular hemodynamic study, and measurements of contractility and the Ca²⁺ transient in isolated adolescent and neonatal cardiomyocytes. After 16 h of LPS treatment, cultured neonatal cardiomyocytes showed a diminished Ca²⁺ transient amplitude associated with an increase in the β₃-AR level. With the addition of a β₃-AR agonist, the Ca²⁺ transient in LPS-treated neonatal rat cardiomyocytes gradually decreased over time; such a change was absent in cells treated with nitric oxide synthase (NOS) inhibitors prior to treatment with a β₃-AR agonist. In adolescent rats with septic myocardial depression, cardiac function declined as indicated by decreased MAP, dP/dt_max, and dP/dt_mix for 6 h after LPS injection; however, the β₃-AR level first increased 2 h after LPS treatment and then decreased 6 h after LPS treatment in the absence of exogenous catecholamines. The results indicate that, in vitro, at the cellular level β₃-AR may be involved in the development of myocardial depression (Ca²⁺ transient depression) in sepsis through NOS signaling pathways; however, in vivo, a complicated mechanism for modulating β₃-AR may exist.

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The Rho kinase inhibitor, fasudil, ameliorates diabetes-induced cardiac dysfunction by improving calcium clearance and actin remodeling

Cited by 32 publications

References 42 publications

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

The RhoA/ROCK pathway mediates high glucose‐induced cardiomyocyte apoptosis via oxidative stress, JNK, and p38MAPK pathways

The Trend of β<sub>3</sub>-Adrenergic Receptor in the Development of Septic Myocardial Depression: A Lipopolysaccharide-Induced Rat Septic Shock Model

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