Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

Abstract

Pronounced variability in blood pressure (BP) is an aggravating factor of hypertensive end-organ damage. However, its pathogenesis remains unknown. Statins have various protective effects on the cardiovascular system. Thus, we determined whether simvastatin would attenuate the aggravation of hypertensive cardiac remodeling in a rat model of hypertension with large BP variability, and also investigated the signaling mechanism involved in its effect. A model of hypertension with large BP variability was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). A SAD or sham operation was performed in 12-week-old rats. Thereafter, simvastatin (0.2 mg kg À1 per day) or vehicle was intraperitoneally administered every day. After 6 weeks , telemetric recordings revealed that SAD enhanced BP variability without changing the mean BP. SAD increased myocyte hypertrophy, myocardial fibrosis and macrophage infiltration associated with the upregulation of brain natriuretic peptide (BNP), type I procollagen, transforming growth factor (TGF)-b and monocyte chemoattractant protein (MCP)-1, and activation of RhoA, Ras and ERK1/2. Simvastatin did not change the mean BP or BP variability in SAD-operated SHRs. In SAD-operated SHRs, simvastatin attenuated myocyte hypertrophy and BNP expression, as well as RhoA, Ras and ERK1/2 activities. In contrast, simvastatin did not change myocardial fibrosis, macrophage infiltration, or the expression of procollagen and TGF-b or MCP-1 in SAD-operated SHRs. Simvastatin did not affect serum lipid levels. In conclusion, simvastatin attenuated the large BP variability-induced aggravation of cardiac hypertrophy, but not myocardial fibrosis, in SHRs. The activation of RhoA/Ras-ERK pathways may contribute to the aggravation of cardiac hypertrophy by a combination of hypertension and large BP variability.

Regulation of Cell Physiology and Pathology by Protein S-Glutathionylation: Lessons Learned from the Cardiovascular System

“…Compared with wild-type animals, those without thioredoxin had greater cardiac hypertrophy, while over-expression of the protein resulted in attenuated cardiac size. The mechanism appeared to be due to modulation of p21Ras at Cys-118 as demonstrated by in vitro models of strain and alpha-adrenergic receptor stimulated cardiac hypertrophy in cardiomyocytes (91,122,157). The modification of p21Ras likely occurs at Cys-118 and supports a mechanism of p21Ras S-nitrosation, followed by an exchange reaction, which leaves p21Ras S-glutathionylated.…”

Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

“…LV fractional shortening and the early to late filling velocity ratio (E/A) were measured at Day 28 using an echocardiograph equipped with a 10-MHz transducer (Aloka, Tokyo, Japan). 11,22,23 Hemodynamic measurement. At Day 28, rats (n¼7 per group) were intraperitoneally anesthetized with 15 mg kg À1 pentobarbital.…”

Large Blood Pressure Variability Aggravates Arteriolosclerosis and Cortical Sclerotic Changes in the Kidney in Hypertensive Rats

“…15,16,18,19 In this model, BPV is increased by approximately 1.5-to 2-fold without the changes in the averages of SBP and mean BP and the pulse pressure. It is known that the sympathetic nerve system and humoral factors, such as angII, are transiently activated at the time of SAD and thereafter the activation wanes within a couple of weeks, 28,29 which might lead to acute organ damage.…”

“…Candesartan shown that the activation of the local angII system participates in the aggravation of hypertensive cardiac remodeling, because SAD did not change the circulating levels of norepinephrine, active renin, and aldosterone and the cardiac norepinephrine content in this model. 14, 18 Thus, we hypothesized that the local angII system might be involved in renal damage induced by the combination of hypertension and large BPV, as well. To determine the direct effects of the angII type 1 receptor blocking, independently of its BP-lowering effect, the maximum dose of candesartan that did not reduce the mean BP was used in this study.…”