Possible Involvement of Rho-Kinase in Aldosterone-Induced Vascular Smooth Muscle Cell Remodeling

Miyata, Kayoko; Hitomi, Hirofumi; Guo, Ping; Zhang, Guo Xing; Kimura, Shoji; Kiyomoto, Hideyasu; Hosomi, Naohisa; Kubo, Shoji; Kohno, Masakazu; Nishiyama, Akira

doi:10.1291/hypres.31.1407

Cited by 25 publications

(18 citation statements)

References 37 publications

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“…17–19 It has been reported that aldosterone also stimulates ROCK activity through binding to the mineralocorticoid receptor in vascular smooth muscle cells and cardiomyocytes. 40,41 ROCK activity is elevated in rats with aldosterone-induced hypertension, leading to vascular remodeling and tissue injury in the heart and kidney. 29,42 In addition, treatment with mineralocorticoid receptor blockers prevented cardiovascular injury through inhibition of ROCK activity in these animal models.…”

Section: Discussionmentioning

confidence: 99%

Effect of Aldosterone-Producing Adenoma on Endothelial Function and Rho-Associated Kinase Activity in Patients With Primary Aldosteronism

et al. 2015

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The purpose of this study was to evaluate vascular function and activity of Rho-associated kinases in patients with primary aldosteronism. Vascular function, including flow-mediated vasodilation and nitroglycerine-induced vasodilation, and Rho-associated kinase activity in peripheral leukocytes were evaluated in 21 patients with aldosterone-producing adenoma, 23 patients with idiopathic hyperaldosteronism, and 40 age-, gender-, and blood pressure-matched patients with essential hypertension. Flow-mediated vasodilation was significantly lower in the aldosterone-producing adenoma group than in the idiopathic hyperaldosteronism and essential hypertension groups (3.2±2.0% vs. 4.6±2.3% and 4.4±2.2%, P<0.05, respectively), whereas there was no significant difference in flow-mediated vasodilation between the idiopathic hyperaldosteronism and essential hypertension groups. There was no significant difference in nitroglycerine-induced vasodilation in the three groups. Rho-associated kinase activity was higher in the aldosterone-producing adenoma group than in the idiopathic hyperaldosteronism and essential hypertension groups (1.29±0.57 vs. 1.00±0.46 and 0.81±0.36, P<0.05, respectively), whereas there was no significant difference in Rho-associated kinase activity between the idiopathic hyperaldosteronism and essential hypertension groups. Flow-mediated vasodilation correlated with age (r=−0.31, P<0.01), plasma aldosterone concentration (r=−0.35, P<0.01) and aldosterone to renin ratio (r=−0.34, P<0.01). Rho-associated kinase activity correlated with age (r=−0.24, P=0.04), plasma aldosterone concentration (r=0.33, P<0.01) and aldosterone to renin ratio (r=0.46, P<0.01). After adrenalectomy, flow-mediated vasodilation and Rho-associated kinase activity were restored in aldosterone-producing adenoma patients. Aldosterone-producing adenoma was associated with both endothelial dysfunction and increased Rho-associated kinase activity compared with those in idiopathic hyperaldosteronism and essential hypertension. Aldosterone-producing adenoma may have a higher risk of future cardiovascular events.

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Section: Discussionmentioning

confidence: 99%

Effect of Aldosterone-Producing Adenoma on Endothelial Function and Rho-Associated Kinase Activity in Patients With Primary Aldosteronism

et al. 2015

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“…26 -28 In vascular smooth muscle cells, aldo enhances Ang II-induced extracellular signal-regulated kinase and JNK phosphorylation 26 -29 and signaling through the RhoA/Rho kinase pathway. 29,30 Pharmacological antagonism of EGFR activity with AG1478 prevents these effects, highlighting the potential role of EGFR activation. In nonvascular cells, such as Madin-Darby canine kidney cells overexpressing the MR, mitogen-activated protein kinase activation by aldo is also EGFR dependent.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

et al. 2011

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Abstract-Pathophysiological aldosterone (aldo)/mineralocorticoid receptor signaling has a major impact on the cardiovascular system, resulting in hypertension and vascular remodeling. Mineralocorticoids induce endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine and increasing the response to vasoconstrictors. Activation of the epidermal growth factor receptor (EGFR) is thought to mediate the vascular effects of aldo, but this has yet to be demonstrated in vivo. In this study, we analyzed the molecular and functional vascular consequences of aldo-salt challenge in the waved 2 mouse, a genetic model with a partial loss of EGFR tyrosine kinase activity. Deficient EGFR activity is associated with global oxidative stress and endothelial dysfunction. A decrease in EGFR activity did not affect the arterial wall remodeling process induced by aldo-salt. By contrast, normal EGFR activity was required for the aldo-induced enhancement of phenylephrine-and angiotensin II-mediated vasoconstriction. In conclusion, this in vivo study demonstrates that EGFR plays a key role in aldosterone-mediated vascular reactivity. Clinical trials (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study and Randomized Aldactone Evaluation Study) have demonstrated the beneficial effects of administering low doses of pharmacological antagonists of the mineralocorticoid receptor (MR; the receptor of the mineralocorticoid hormone aldosterone [aldo]) to patients with heart failure, with improvements in survival rate and morbidity. 1,2 These clinical benefits may partly result from improved vascular function. 3 The MR is expressed in both endothelium and smooth muscle, 4 and the vessels are now considered to be direct targets of aldo. 5 In the mouse, the 11␤-hydroxysteroid dehydrogenase type II enzyme is expressed in the endothelium but not in the smooth muscle, 4,6 at variance with humans. 7 Therefore, in the mouse, aldo is the specific ligand of the MR in the endothelium but not in the smooth muscle, where glucocorticoids could also activate MR. MR activation affects endothelial function and vascular tone: aldo infusion induces endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine (Ach), and increasing the response to various vasoconstrictors. 5,8,9 We showed recently that an increase in MR signaling in the endothelium is associated with an increase in blood pressure and altered vascular tone. 4 Moreover, patients with primary aldosteronism have a higher aortic wall thickness than those with primary hypertension. 10 Aldo is, thus, recognized as a cardiovascular risk factor that exacerbates vascular injury, 3 although the underlying mechanisms remain unclear.It has been suggested that the epidermal growth factor receptor (EGFR) could play a key role in the cardiovascular effects of aldo. 11 In cultured cells, downstream EGFR signaling cascades are induced by aldo or prevented by MR blockade on aldo stimulation. 12 Increases in EGFR expression and/or activation have...

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“…As a consequence, aldosterone induced VSMC stress fiber formation and migration. All of these effects were blocked by eplerenone, a selective MR blocker, and Y27632, a specific Rho-kinase inhibitor [10]. …”

Section: Effects Of Aldosterone On Vascular Remodelingmentioning

confidence: 99%

Vascular Actions of Aldosterone

2012

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Aldosterone exerts direct effects on the vascular system by inducing oxidative stress, inflammation, hypertrophic remodeling, fibrosis, and endothelial dysfunction. Aldosterone exerts its effects through genomic and nongenomic pathways in a mineralocorticoid receptor (MR)-dependent or independent manner. Other aldosterone receptors such as GPR30 have been identified. A tight relation exists between the aldosterone and angiotensin II pathways, as well as with the endothelin-1 system. There is a correlation between plasma levels of aldosterone and cardiovascular risk. Recently, an increasing body of evidence has underlined the importance of aldosterone in cardiovascular complications associated with the metabolic syndrome, such as arterial remodeling and endothelial dysfunction. Blockade of MR is an increasingly used evidence-based therapy for many forms of cardiovascular disease, including hypertension, heart failure, chronic kidney disease, and diabetes mellitus.

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Possible Involvement of Rho-Kinase in Aldosterone-Induced Vascular Smooth Muscle Cell Remodeling

Cited by 25 publications

References 37 publications

Effect of Aldosterone-Producing Adenoma on Endothelial Function and Rho-Associated Kinase Activity in Patients With Primary Aldosteronism

Effect of Aldosterone-Producing Adenoma on Endothelial Function and Rho-Associated Kinase Activity in Patients With Primary Aldosteronism

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

Vascular Actions of Aldosterone

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