Effects of a Rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction

2008 ◽  
Vol 294 (4) ◽  
pp. H1804-H1814 ◽  
Author(s):  
Arintaya Phrommintikul ◽  
Lavinia Tran ◽  
Andrew Kompa ◽  
Bing Wang ◽  
Anastasia Adrahtas ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Diastolic Dysfunction ◽  
Kinase Inhibitor ◽  
Diastolic Pressure ◽  
Rho Kinase ◽  
Pressure Overload ◽  
Rock Inhibitor ◽  
Abdominal Aortic ◽  
Vehicle Treatment ◽  
Rock Inhibition

The RhoA-Rho kinase (ROCK) signaling pathway has an important role in cardiovascular diseases. However, the effect of Rho kinase inhibition on pressure overload-induced cardiac hypertrophy (POH) and associated diastolic dysfunction has not been evaluated. This study examined the effect of a selective ROCK inhibitor (GSK-576371) in a POH model, induced by suprarenal abdominal aortic constriction. POH rats were divided into the following four groups: 1 (GSK 1, n = 9) or 3 (GSK 3, n = 10) mg/kg bid GSK-576371, 1 mg·kg−1·day−1 ramipril ( n = 10) or vehicle ( n = 11) treatment for 4 wk. Sham animals ( n = 11) underwent surgery without banding. Echocardiograms were performed before surgery and posttreatment, and hemodynamic data were obtained at completion of the study. Echocardiography showed an increase in relative wall thickness of the left ventricle (LV) following POH + vehicle treatment compared with sham animals. This was attenuated by both doses of GSK-576371 and ramipril. Vehicle treatment demonstrated abnormal diastolic parameters, including mitral valve (MV) inflow E wave deceleration time, isovolumic relaxation time, and MV annular velocity, which were dose dependently restored toward sham values by GSK-576371. LV end diastolic pressure was increased following POH + vehicle treatment compared with sham (6.9 ± 0.7 vs. 3.2 ± 0.7 mmHg, P = 0.008) and was reduced with GSK 3 and ramipril treatment (1.7 ± 0.7, P < 0.01 and 2.9 ± 0.6 mmHg, P < 0.01, respectively). Collagen I deposition in the LV was increased following POH + vehicle treatment (32.2%; P < 0.01) compared with sham animals and was significantly attenuated with GSK 1 (21.7%; P < 0.05), GSK 3 (23.8%; P < 0.01), and ramipril (35.5%; P < 0.01) treatment. These results suggest that ROCK inhibition improves LV geometry and reduces collagen deposition accompanied by improved diastolic function in POH.

Organized migration of epithelial cells requires control of adhesion and protrusion through Rho kinase effectors

2007 ◽  
Vol 292 (3) ◽  
pp. G806-G817 ◽  
Author(s):  
Ann M. Hopkins ◽  
A’Drian A. Pineda ◽  
L. Matthew Winfree ◽  
G. Thomas Brown ◽  
Mike G. Laukoetter ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Leading Edge ◽  
Dominant Negative ◽  
Actin Binding ◽  
Rock Inhibitor ◽  
Cell Sheets ◽  
Lim Kinase ◽  
Rock Inhibition

Migration of epithelial cell sheets, a process involving F-actin restructuring through Rho family GTPases, is both physiologically and pathophysiologically important. Our objective was to clarify the mechanisms whereby the downstream RhoA effector Rho-associated coil-coil-forming kinase (ROCK) influences coordinated epithelial cell motility. Although cells exposed to a pharmacological ROCK inhibitor (Y-27632) exhibited increased spreading in wound closure assays, they failed to migrate in a cohesive manner. Two main phenomena were implicated: the formation of aberrant protrusions at the migrating front and the basal accumulation of F-actin aggregates. Aggregates reflected increased membrane affiliation and detergent insolubility of the actin-binding protein ezrin and enhanced coassociation of ezrin with the membrane protein CD44. While F-actin aggregation following ROCK inhibition was recapitulated by inhibiting myosin light chain (MLC) phosphorylation with the MLC kinase inhibitor ML-7, the latter did not influence protrusiveness and, in fact, significantly decreased cell migration. Our results suggest that excessive protrusiveness downstream of ROCK inhibition reflects an influence of ROCK on F-actin stability via LIM kinase 1 (LIMK-1), which phosphorylates and inactivates cofilin. Y-27632 reduced the levels of both active LIMK-1 and inactive cofilin (phospho forms), and expression of a dominant negative LIMK-1 mutant stimulated leading edge protrusiveness. Furthermore, Y-27632-induced protrusions were partially reversed by overexpression of LIMK-1 to restore cofilin phosphorylation. In summary, our results provide new evidence suggesting that adhesive and protrusive events involved in organized epithelial motility downstream of ROCK are separately coordinated through the phosphorylation of (respectively) MLC and cofilin.

scholarly journals Leonurine Attenuates Pressure-Overload Cardiac Hypertrophy Induced By Abdominal Aortic Constriction In Rats

2021 ◽  
Author(s):  
Ding Xiaoli ◽  
Yuan Qingqing ◽  
Qian Haibing
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Ang Ii ◽  
Aortic Constriction ◽  
Qrt Pcr ◽  
Abdominal Aortic

Abstract Background: Myocardial hypertrophy occurs in many cardiovascular diseases. Leonurine (Leo) is commonly used for cardiovascular and cerebrovascular diseases. However, whether it can prevent cardiac hypertrophy is not known. The aim of this study was to investigate the effect and mechanism of Leonurine (Leo) against pressure-overload cardiac hypertrophy induced by abdominal aortic constriction (AAC) in rats. Methods: To answer this question, we prove it in the following way: Cardiac function was evaluated by hemodynamic; the left ventricle enlargement was measured by heart weight index (HWI) and left ventricular mass index (LVWI); myocardial tissue changes and myocardial cell diameter (MD) were determined by Hematoxylin and eosin (HE) staining; theβ-myosin heavy chain(β-MHC)and atrial natriuretic factor (ANF), which are recognized as a marker of cardiac hypertrophy, were determined by Real-time quantitative PCR (qRT-PCR), then another gene phospholipase C (PLC), inositol triphosphate (IP3), which associated with RAS were determined by Western blot(WB). angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R) were determined by ELISA, WB and qRT-PCR methods. Finally, we measured the level of Ca2+ by microplate method and the protooncogene c-fos and c-myc mRNA in left ventricular myocardium by qRT-PCR.Results: Compare with control group, Leonurine can improve systolic dysfunction; inhibit the increase of left cardiac; inhibit myocardial cells were abnormally large and restrain the changes of cardiac histopathology; decrease the expression of β-MHC, ANF, Ang II, AT1R, c-fos and c-myc mRNA and the protein levels of PLC, IP3, AngII and AT1R in left ventricular myocardium, in addition, the content of Ca2+ also decrease. Conclusion: Therefore, Leonurine can inhibit cardiac hypertrophy induced by AAC and its effects may be associated with RAS.

A visible light-controllable Rho kinase inhibitor based on a photochromic phenylazothiazole

2021 ◽  
Author(s):  
Kazuya Matsuo ◽  
Sampreeth Thayyil ◽  
Mitsuyasu Kawaguchi ◽  
Hidehiko Nakagawa ◽  
Nobuyuki Tamaoki
Keyword(s):  
Protein Kinase ◽  
Visible Light ◽  
Kinase Inhibitor ◽  
Coiled Coil ◽  
Rho Kinase ◽  
Rock Inhibitor ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Rho Kinase Inhibitor

Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine-threonine kinase, whose inhibitors are useful for the regulation of actomyosin system. Here, we developed a photoswitchable ROCK inhibitor based on a phenylazothiazole...

Diverse regulation of IP3 and ryanodine receptors by pentazocine through σ1-receptor in cardiomyocytes

2013 ◽  
Vol 305 (8) ◽  
pp. H1201-H1212 ◽  
Author(s):  
Hideaki Tagashira ◽  
Md. Shenuarin Bhuiyan ◽  
Kohji Fukunaga
Keyword(s):  
Cardiac Hypertrophy ◽  
Diastolic Pressure ◽  
Ryanodine Receptors ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Female Rats ◽  
In Vivo Studies ◽  
Atp Production ◽  
Cultured Cardiomyocytes

Although pentazocine binds to σ1-receptor (σ1R) with high affinity, the physiological relevance of its binding remains unclear. We first confirmed that σ1R stimulation with pentazocine rescues contractile dysfunction following pressure overload (PO)-induced cardiac hypertrophy ovariectomized (OVX) female rats. In in vivo studies, vehicle, pentazocine (0.5–1.0 mg/kg ip), and NE-100 (1.0 mg/kg po), a σ1R antagonist, were administered for 4 wk (once daily) starting from the onset of aortic banding after OVX. We also examined antihypertrophic effects of pentazocine (0.5–1 μM) in cultured cardiomyocytes exposed to angiotensin II. Pentazocine administration significantly inhibited PO-induced cardiac hypertrophy and rescued hypertrophy-induced impairment of cardiac dysfunctions such as left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular contraction and relaxation (±dp/dt) rates. Coadministration of NE-100 with pentazocine eliminated pentazocine-induced amelioration of heart dysfunction. Interestingly, pentazocine administration inhibited PO-induced σ1R reduction and inositol-1,4,5-trisphosphate (IP3) receptor type 2 (IP3R2) upregulation in heart. Therefore, the reduced mitochondrial ATP production following PO was restored by pentazocine administration. Furthermore, we found that σ1R binds to the ryanodine receptor (RyR) in addition to IP3 receptor (IP3R) in cardiomyocytes. The σ1R/RyR complexes were decreased following OVX-PO and restored by pentazocine administration. We noticed that pentazocine inhibits the ryanodine-induced Ca2+ release from sarcoplasmic reticulum (SR) in cultured cardiomyocytes. Taken together, the stimulation of σ1R by pentazocine rescues cardiac dysfunction by restoring IP3R-mediated mitochondrial ATP production and by suppressing RyR-mediated Ca2+ leak from SR in cardiomyocytes.

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

2018 ◽  
Vol 115 (30) ◽  
pp. E7129-E7138 ◽  
Author(s):  
Shinichiro Sunamura ◽  
Kimio Satoh ◽  
Ryo Kurosawa ◽  
Tomohiro Ohtsuki ◽  
Nobuhiro Kikuchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Hypertension ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
High Throughput Screening ◽  
Histological Analysis ◽  
Rho Kinase ◽  
Pressure Overload ◽  
Aortic Constriction ◽  
Patients With Heart Failure

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 (cROCK1−/−) and ROCK2-deficient (cROCK2−/−) 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 cROCK1−/− mice compared with controls, whereas cardiac hypertrophy was attenuated in cROCK2−/− mice after TAC. Consistently, the levels of oxidative stress were up-regulated in cROCK1−/− hearts and down-regulated in cROCK2−/− 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 cROCK1−/− mice, whereas their expressions were significantly lower in cROCK2−/− 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.

Altered renal dopamine receptors during development of cardiac hypertrophy

1992 ◽  
Vol 262 (5) ◽  
pp. E569-E573
Author(s):  
P. K. Ganguly ◽  
K. Mukherjee ◽  
Y. Chen
Keyword(s):  
Cardiac Hypertrophy ◽  
Dopamine Receptors ◽  
Pressure Overload ◽  
Total Body Weight ◽  
Left Ventricular ◽  
Kidney Cortex ◽  
Sprague Dawley ◽  
Aortic Constriction ◽  
Compensatory Response ◽  
Abdominal Aortic

The characteristics of dopamine receptors were studied in heart and kidney using the radiolabeled receptor assay of [3H]spiperone during the development of cardiac hypertrophy. Male Sprague-Dawley rats (175-200 g) underwent abdominal aortic constriction above the renal arteries and were studied 3, 14, and 28 days thereafter. Sham-operated animals without aortic constriction were used as control. Although the ratio of left ventricular weight to total body weight was significantly increased 14 and 28 days after aortic constriction in animals, [3H]spiperone binding in left ventricular membrane was increased as early as 3 days after aortic constriction. At 14 days, the binding was still elevated and, by 28 days, it returned to control values. In contrast, membranes obtained from kidney cortex showed an elevation of [3H]spiperone binding only at 28 days after aortic constriction; at 3 days the binding values were decreased. A reciprocal correlation was found between the number of dopamine receptors and the activity of Na(+)-K(+)-ATPase at 28 days of aortic constriction; the enzyme activity, as measured by the release of 32Pi from [gamma-32P]ATP, was decreased in kidney cortex. Autoradiographic data also showed an increased number of dopamine receptors in kidney at 28 days after abdominal aortic constriction. These results suggest that the dopamine receptor is increased very early in heart in response to pressure overload as a result of a compensatory response to maintain an optimal left ventricular output. Kidney dopamine receptors are triggered at a later stage possibly to maintain fluid homeostasis secondary to the cardiac hypertrophic process.

scholarly journals Physiological Induction of a β-Adrenergic Receptor Kinase Inhibitor Transgene Preserves β-Adrenergic Responsiveness in Pressure-Overload Cardiac Hypertrophy

Circulation ◽  
2000 ◽  
Vol 102 (22) ◽  
pp. 2751-2757 ◽  
Author(s):  
Brian S. Manning ◽  
Kyle Shotwell ◽  
Lan Mao ◽  
Howard A. Rockman ◽  
Walter J. Koch
Keyword(s):  
Cardiac Hypertrophy ◽  
Adrenergic Receptor ◽  
Kinase Inhibitor ◽  
Pressure Overload ◽  
Receptor Kinase

Abstract 17904: Deficiency of Yes-associated Protein Promotes Cardiac Dysfunction in Response to Pressure Overload in the Mouse Heart

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jaemin Byun ◽  
Dominic P Del Re ◽  
Peiyong Zhai ◽  
Akihiro Shirakabe ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Mammalian Cells ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Pressure Overload ◽  
Wall Stress ◽  
Left Ventricular ◽  
Lv Function ◽  
Mouse Heart ◽  
And Control

Yes-Associated Protein (YAP), a downstream effector of the Hippo pathway, plays an important role in regulating cell proliferation and survival in mammalian cells. We have shown that cardiac-specific loss of YAP leads to increased cardiomyocyte (CM) apoptosis and impaired hypertrophy during chronic myocardial infarction in the mouse heart. However, it remains unclear whether YAP mediates hypertrophy of individual CMs under stress conditions in vivo. We hypothesized that endogenous YAP plays an essential role in mediating hypertrophy and survival of CMs in response to pressure overload (PO). Three-month-old YAP+/fl;α-MHC-Cre (YAP-cKO) and YAP+/fl (control) mice were subjected to transverse aortic constriction (TAC). Two weeks later, YAP-cKO and control mice developed similar levels of cardiac hypertrophy (left ventricular (LV) weight/tibia length: 7.27±0.38, 6.93±0.29) compared to sham (5.08±0.14, 4.07±0.33). LV CM cross sectional area was similarly increased by TAC in YAP-cKO and control mice compared to their respective shams. Induction of fetal-type genes, such as Anf and Myh7, was also similar in YAP-cKO and control mice. YAP-cKO and control mice exhibited similar baseline LV systolic function (ejection fraction (EF): 75, 76%). YAP-cKO mice had significantly decreased LV function after TAC compared to Sham-control mice (EF: 51%, 76%, p<0.05) and TAC-control mice (75%, p<0.05). LV end diastolic pressure (LVEDP, mmHg) was significantly increased (19.3 ±3.2, 9.8±1.6, p<0.05), and LV +dP/dt (mmHg/s, 7250±588, 9500±453, p<0.01) and -dP/dt (mmHg/s, 6000±433, 7781± 314, p<0.05) were significantly decreased in YAP-cKO compared to in control mice after TAC. LV end diastolic diameter (mm) was significantly greater in YAP-cKO than in control mice after TAC (3.95±0.11, 3.35±0.15, p<0.05), whereas LV pressure was similar, suggesting that LV wall stress was elevated in YAP-cKO compared to in control mice. Since cardiac hypertrophy in YAP-cKO mice is similar to that in control mice despite elevated wall stress, the lack of YAP appears to limit the extent of cardiac hypertrophy in response to increased wall stress. These data suggest that endogenous YAP plays an important role in mediating adaptive hypertrophy and protecting the heart against PO.

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