Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction

Shimizu, Tôru; Narang, Nikhil; Chen, Phetcharat; Yu, Brian; Knapp, Maura; Janardanan, Jyothi; Blair, John E.; Liao, James K.

doi:10.1172/jci.insight.93187

Cited by 61 publications

(50 citation statements)

References 58 publications

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“…This is consistent with the previous reports indicating that myocardial ROCK2 promotes the development of angiotensin II (AngII)-induced cardiac hypertrophy (22). Moreover, a recent study demonstrated that cardiac fibroblasts-specific ROCK2 deficiency protects the heart against the development of AngIIinduced cardiac hypertrophy and fibrosis (37). Thus, selective ROCK2 inhibition may be a suitable therapeutic strategy for HFpEF, which is characterized by enhanced cardiac hypertrophy and fibrosis.…”

Section: Discussionsupporting

confidence: 92%

“…In contrast, cROCK2 −/− mice showed decreased cardiac hypertrophy compared with littermate controls after TAC. Furthermore, ROCK2 in cardiac fibroblasts is necessary to cause cardiac hypertrophy and fibrosis (37). It has recently been demonstrated that a selective ROCK2 inhibitor, KD025, could be an effective treatment for ischemic stroke and autoimmune diseases (50,51).…”

Section: Celastrol As a Novel Therapeutic Agent For Hf Patients With mentioning

confidence: 99%

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Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

Sunamura

Satoh

Kurosawa

et al. 2018

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

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Although postcapillary pulmonary hypertension (PH) is an important prognostic factor for patients with heart failure (HF), its pathogenesis remains to be fully elucidated. To elucidate the different roles of Rho-kinase isoforms, ROCK1 and ROCK2, in cardiomyocytes in response to chronic pressure overload, we performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient () and ROCK2-deficient () mice. Cardiomyocyte-specific ROCK1 deficiency promoted pressure-overload-induced cardiac dysfunction and postcapillary PH, whereas cardiomyocyte-specific ROCK2 deficiency showed opposite results. Histological analysis showed that pressure-overload-induced cardiac hypertrophy and fibrosis were enhanced in mice compared with controls, whereas cardiac hypertrophy was attenuated in mice after TAC. Consistently, the levels of oxidative stress were up-regulated in hearts and down-regulated in hearts compared with controls after TAC. Furthermore, cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary PH in mice, whereas their expressions were significantly lower in mice. In clinical studies, plasma levels of CyPA were significantly increased in HF patients and were higher in patients with postcapillary PH compared with those without it. Finally, high-throughput screening demonstrated that celastrol, an antioxidant and antiinflammatory agent, reduced the expressions of CyPA and Bsg in the heart and the lung, ameliorating cardiac dysfunction and postcapillary PH induced by TAC. Thus, by differentially affecting CyPA and Bsg expressions, ROCK1 protects and ROCK2 jeopardizes the heart from pressure-overload HF with postcapillary PH, for which celastrol may be a promising agent.

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Section: Discussionsupporting

confidence: 92%

Section: Celastrol As a Novel Therapeutic Agent For Hf Patients With mentioning

confidence: 99%

Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

Sunamura

Satoh

Kurosawa

et al. 2018

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

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“…As an effector of RhoA, ROCK2 has been reported to mediate ANG II-induced cardiac hypertrophy via its substrate, formin homology 2 domain containing 3 (FHOD3), which is a cardiacrestricted member of diaphanous-related formins crucial in regulating myofibrillogenesis in cardiomyocytes (1272). However, cardiac fibroblast ROCK2 may also mediate cardiac hypertrophy and fibrosis induced by ANG II through a paracrine mechanism involving CTGF and FGF2 (952). G protein-dependent MAPK/ERK kinase (MEK)-ERK1/2 signaling is also under negative regulation by regulator of G protein signaling 3 (RGS3) and RGS5, which attenuate cardiac hypertrophy in vivo from aortic banding or in vitro from ANG II (564,603).…”

Section: Ang II In Cardiac Hypertrophymentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

816

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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“…Profibrotic ROCK activity, however, is not only restricted to cardiomyocytes. ROCK2 expression in activated fibroblasts was shown to promote cardiac fibrosis in mice receiving continuous angiotensin II infusions [26]. All these data clearly point to an active role of ROCKs in cardiac fibrogenesis in noninflammatory condition.…”

mentioning

confidence: 87%

Haploinsufficient Rock1+/− and Rock2+/− Mice Are Not Protected from Cardiac Inflammation and Postinflammatory Fibrosis in Experimental Autoimmune Myocarditis

Tkacz

Rolski

Czepiel

et al. 2020

Cells

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Progressive cardiac fibrosis is a common cause of heart failure. Rho-associated, coiled-coil-containing protein kinases (ROCKs) have been shown to enhance fibrotic processes in the heart and in other organs. In this study, using wild-type, Rock1+/− and Rock2+/− haploinsufficient mice and mouse model of experimental autoimmune myocarditis (EAM) we addressed the role of ROCK1 and ROCK2 in development of myocarditis and postinflammatory fibrosis. We found that myocarditis severity was comparable in wild-type, Rock1+/− and Rock2+/− mice at day 21 of EAM. During the acute stage of the disease, hearts of Rock1+/− mice showed unaffected numbers of CD11b+CD36+ macrophages, CD11b+CD36–Ly6GhiLy6chi neutrophils, CD11b+CD36–Ly6G–Ly6chi inflammatory monocytes, CD11b+CD36–Ly6G–Ly6c– monocytes, CD11b+SiglecF+ eosinophils, CD11b+CD11c+ inflammatory dendritic cells and type I collagen-producing fibroblasts. Isolated Rock1+/− cardiac fibroblasts treated with transforming growth factor-beta (TGF-β) showed attenuated Smad2 and extracellular signal-regulated kinase (Erk) phosphorylations that were associated with impaired upregulation of smooth muscle actin alpha (αSMA) protein. In contrast to cardiac fibroblasts, expanded Rock1+/− heart inflammatory myeloid cells showed unaffected Smad2 activation but enhanced Erk phosphorylation following TGF-β treatment. Rock1+/− inflammatory cells responded to TGF-β by a reduced transcriptional profibrotic response and failed to upregulate αSMA and fibronectin at the protein levels. Unexpectedly, in the EAM model wild-type, Rock1+/− and Rock2+/− mice developed a similar extent of cardiac fibrosis at day 40. In addition, hearts of the wild-type and Rock1+/− mice showed comparable levels of cardiac vimentin, periostin and αSMA. In conclusion, despite the fact that ROCK1 regulates TGF-β-dependent profibrotic response, neither ROCK1 nor ROCK2 is critically involved in the development of postinflammatory fibrosis in the EAM model.

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Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction

Cited by 61 publications

References 58 publications

Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Haploinsufficient Rock1+/− and Rock2+/− Mice Are Not Protected from Cardiac Inflammation and Postinflammatory Fibrosis in Experimental Autoimmune Myocarditis

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