Effect of Early Normotension with Olmesartan on Rho-kinase Activity in Hypertensive Patients

Cantin, Claudio; Jalil, Jorge; Bulnes, Juan F.; Novoa, Ulises; MacNab, Paul; Godoy, Iván; Córdova, Samuel; Gabrielli, Luigi; Ocaranza, María Paz

doi:10.2174/1570161117666190121103116

Cited by 3 publications

(1 citation statement)

References 16 publications

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“…Interestingly, in DOCA salt hypertensive rats, ROCK activity determined in circulating leukocytes reflects the activation of this pathway in the myocardium and is related to myocardial remodeling (hypertrophy, fibrosis and inflammation) 33 which contributes to explain the biological significance of increased ROCK activation in circulating leukocytes in clinical hypertension. 54 -56…”

Section: Discussionmentioning

confidence: 99%

Hydrochlorothiazide Reduces Cardiac Hypertrophy, Fibrosis and Rho-Kinase Activation in DOCA-Salt Induced Hypertension

Mondaca‐Ruff

Araos

Yáñez

et al. 2021

J Cardiovasc Pharmacol Ther

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Background: Thiazides are one of the most common antihypertensive drugs used for hypertension treatment and hydrochlorothiazide (HCTZ) is the most frequently used diuretic for hypertension treatment. The Rho/Rho-kinase (ROCK) path plays a key function in cardiovascular remodeling. We hypothesized that in preclinical hypertension HCTZ reduces myocardial ROCK activation and consequent myocardial remodeling. Methods: The preclinical model of deoxycorticosterone (DOCA)-salt hypertension was used (Sprague–Dawley male rats). After 3 weeks, in 3 different groups: HCTZ, the ROCK inhibitor fasudil or spironolactone was added (3 weeks). After 6 weeks myocardial hypertrophy and fibrosis, cardiac levels of profibrotic proteins, mRNA levels (RT PCR) of pro remodeling and pro oxidative molecules and ROCK activity were determined. Results: Blood pressure, myocardial hypertrophy and fibrosis were reduced significantly by HCTZ, fasudil and spironolactone. In the heart, increased levels of the pro-fibrotic proteins Col-I, Col-III and TGF-β1 and gene expression of pro-remodeling molecules TGF-β1, CTGF, MCP-1 and PAI-1 and the pro-oxidative molecules gp91phox and p22phox were significantly reduced by HCTZ, fasudil and spironolactone. ROCK activity in the myocardium was increased by 54% ( P < 0.05) as related to the sham group and HCTZ, spironolactone and fasudil, reduced ROCK activation to control levels. Conclusions: HCTZ reduced pathologic LVH by controlling blood pressure, hypertrophy and myocardial fibrosis and by decreasing myocardial ROCK activation, expression of pro remodeling, pro fibrotic and pro oxidative genes. In hypertension, the observed effects of HCTZ on the myocardium might explain preventive outcomes of thiazides in hypertension, specifically on LVH regression and incident heart failure.

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Section: Discussionmentioning

confidence: 99%

Hydrochlorothiazide Reduces Cardiac Hypertrophy, Fibrosis and Rho-Kinase Activation in DOCA-Salt Induced Hypertension

Mondaca‐Ruff

Araos

Yáñez

et al. 2021

J Cardiovasc Pharmacol Ther

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Urotensin-#receptor antagonist SB-706375 protected isolated rat heart from ischaemia–reperfusion injury by attenuating myocardial necrosis via RhoA/ROCK/RIP3 signalling pathway

et al. 2019

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Rho kinase cascade activation in circulating leukocytes in patients with diabetes mellitus type 2

Ocaranza

Valderas

Moya

et al. 2020

Cardiovasc Diabetol

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Background The intracellular ROCK signaling pathway is an important modulator of blood pressure and of cardiovascular and renal remodeling when Rho-kinase activity is increased. Besides, in preclinical models of diabetes, ROCK activation has also a role in abnormal glucose metabolism as well as in subsequent vascular and myocardial dysfunction. In humans, there are a few data assessing ROCK activation in patients with type 2 diabetes mellitus (T2D) and no studies assessing upstream/downstream components of the ROCK pathway. We assessed here levels of ROCK activation and some of the RhoA/ROCK cascade molecules in peripheral blood mononuclear cells (PBMCs) in T2D patients under current treatment. Methods Cross-sectional observational study comparing 28 T2D patients under current antidiabetic treatment with 31 consecutive healthy subjects, matched by age and gender. Circulating levels of malondialdehyde, angiotensin II and inflammatory cytokines IL-6 and IL-8 were determined in all subjects. ROCK activation in PMBCs, upstream and downstream cascade proteins, and levels of the proinflammatory molecules VCAM, ICAM-1 and IL-8 were determined in their PMBCs by Western blot. Results Compared to healthy controls, ROCK activation in T2D patients measured by 2 direct ROCK targets in PBMCs was increased by 420 and 570% (p < 0001) and it correlated significantly with serum glucose levels. p38 MAPK phosphorylation (downstream from ROCK) and JAK-2 (upstream from ROCK) were significantly higher in the T2D patients by 580% and 220%, respectively. In T2D patients, significantly increased PBMC levels of the proinflammatory molecules VCAM-1, ICAM-1 and IL-8 were observed compared to control subjects (by 180%, 360% and 260%, respectively). Circulating levels of Ang II and MDA were significantly higher in T2D patients by 29 and 63%, respectively. Conclusions T2D patients under treatment with glucose-lowering drugs, antihypertensive treatment as well as with statins have significantly increased ROCK activation in their circulating leukocytes along with higher phosphorylation of downstream cascade proteins despite pharmacologic treatment, along with increased plasma angiotensin II and MDA levels. ROCK inhibition might have an additional role in the prevention and treatment of T2D.

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Effect of Early Normotension with Olmesartan on Rho-kinase Activity in Hypertensive Patients

Cited by 3 publications

References 16 publications

Hydrochlorothiazide Reduces Cardiac Hypertrophy, Fibrosis and Rho-Kinase Activation in DOCA-Salt Induced Hypertension

Hydrochlorothiazide Reduces Cardiac Hypertrophy, Fibrosis and Rho-Kinase Activation in DOCA-Salt Induced Hypertension

Urotensin-#receptor antagonist SB-706375 protected isolated rat heart from ischaemia–reperfusion injury by attenuating myocardial necrosis via RhoA/ROCK/RIP3 signalling pathway

Rho kinase cascade activation in circulating leukocytes in patients with diabetes mellitus type 2

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