Blood pressure variability activates cardiac mineralocorticoid receptor and induces cardiac remodeling in hypertensive rats

Suguru Yasuoka, Hisashi Kai, Hidemi Kajimoto, Hiroshi Kudo, Narimasa Takayama, Takahiro Anegawa, Mitsuhisa Koga, Takanobu Miyamoto, Hiroharu Mifune, Masayoshi Kage, Yoshitaka Hirooka, Tsutomu Imaizumi

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Background: Hypertensive patients with large blood pressure variability (BPV) have aggravated target organ damage. Because the aldosterone/mineralocorticoid receptor (MR) system is a possible mechanism of hypertensive organ damage, we investigated in spontaneously hypertensive rats (SHRs) whether a specific MR blocker, eplere-none, would prevent BPV-induced aggravation of hypertensive cardiac remodeling. Methods and Results: A rat model of a combination of hypertension and large BPV was created by performing bilateral sinoaortic denervation (SAD) in SHRs. SAD increased BPV without changing mean BP. SAD induced perivascular macrophage infiltration and aggravated myocardial fibrosis and cardiac hypertrophy, resulting in LV systolic dysfunction. Immunohistostaining revealed SAD-induced translocation of MRs into the nuclei (ie, MR activation) of the intramyocardial arterial medial cells and cardiac myocytes. SAD increased phosphorylation of p21-acti-vated kinase1 (PAK1), a regulator of MR nuclear translocation. Chronic administration of a subdepressor dose of eplerenone prevented MR translocation, macrophage infiltration, myocardial fibrosis, cardiac hypertrophy, and LV dysfunction, while not affecting BPV. Circulating levels of aldosterone and cortisol were not changed by SAD. Conclusions: Eplerenone inhibited the aggravation of cardiac inflammation and hypertensive cardiac remodeling, and thereby prevented progression of LV dysfunction in SHRs with large BPV. This suggests that the PAK1-MR pathway plays a role in cardiac inflammation and remodeling induced by large BPV superimposed on hypertension, independent of circulating aldosterone.

Original languageEnglish
Pages (from-to)1474-1481
Number of pages8
JournalCirculation Journal
Volume77
Issue number6
DOIs
Publication statusPublished - 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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