Abstract 8973: p21-Activated Kinase-Mineralocorticoid Receptor Pathway Aggravates Cardiac Inflammation and Remodeling in Hypertensive Rats with Large Blood Pressure Variability
Background: Hypertensive patients with large blood pressure variability (BPV) show aggravated end-organ damage. There is increasing evidence that aldosterone contributes to hypertensive organ damage via mineralocorticoid receptor (MR) activation. Recently, Rac-p21-activated kinase (PAK) pathway is highlighted as an activator of MRs in the renal tubular cells. The aims of this study were to investigate whether large BPV would activate MRs in the hearts in SHR and to determine whether a specific MR blocker, eplerenone, at a non-depressor dose would prevent the large BPV-induced aggravation of hypertensive cardiac remodeling.
Methods and Results: SHRs (n=76) were fed with normal salt diet. A rat model of a combination of hypertension and large BPV was created by performing bilateral sinoaortic denervation (SAD) in SHR. SAD increased BPV (P<0.05) without changing mean BP in SHR. Large BPV induced perivascular macrophage infiltration and aggravated myocardial fibrosis and cardiac myocyte hypertrophy, resulting in LV systolic dysfunction (P<0.05 for each). Immunohistostaining revealed the expressions of MR and PAK in the coronary medial cells and to a lesser extent the cardiac myocytes in SHR. Large BPV induced the translocation of the MRs into the nuclei (i.e. MR activation) and increased PAK phosphorylation (i.e. PAK activation) in the coronary medial cells. Chronic administration of a subdepressor dose of eplerenone prevented the MR translocation, macrophage infiltration, myocardial fibrosis, myocyte hypertrophy, and LV dysfunction (P<0.05 for each), while not affecting BPV. Circulating levels of aldosterone, corticosterone, active renin, and angiotensin II were not changed by large BPV in SHR.
Conclusion: Large BPV activated PAK and MR in the coronary medial cells and aggravated perivascular inflammation, cardiac remodeling, and LV dysfunction in SHR, which were prevented by eplerenone. Thus, the PAK-MR pathway activation may play a role in cardiac inflammation and remodeling induced by large BPV superimposed upon hypertension. Eplerenone may be useful for treatment of hypertensives with large BPV.
- © 2011 by American Heart Association, Inc.