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

Narimasa Takayama; Hisashi Kai; Hiroshi Kudo; Suguru Yasuoka; Takahiro Mori; Takahiro Anegawa; Mitsuhisa Koga; Hidemi Kajimoto; Yoshitaka Hirooka; Tsutomu Imaizumi

doi:10.1038/hr.2010.229

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

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

Narimasa Takayama, Hisashi Kai, Hiroshi Kudo, Suguru Yasuoka, Takahiro Mori, Takahiro Anegawa, Mitsuhisa Koga, Hidemi Kajimoto, Yoshitaka Hirooka and Tsutomu Imaizumi

Hypertension research, Vol.34(3), pp.341-347

03/01/2011

DOI: 10.1038/hr.2010.229

PMID: 21124329

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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 mgkg(-1) 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)-β 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-β 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.

Animals

Blood Pressure - drug effects

Cardiomegaly - drug therapy

Cardiomegaly - pathology

Carotid Sinus - innervation

Cell Enlargement - drug effects

Cholesterol - blood

Denervation

Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors

Heart Rate - drug effects

Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use

Hypertension - drug therapy

Lipoproteins, HDL - blood

Male

Monomeric GTP-Binding Proteins - antagonists & inhibitors

Myocytes, Cardiac - drug effects

Myocytes, Cardiac - physiology

Rats

Rats, Inbred SHR

rhoA GTP-Binding Protein - antagonists & inhibitors

Simvastatin - therapeutic use

Treatment Outcome

Triglycerides - blood

Ventricular Remodeling - drug effects

Details

Title: Subtitle: Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras-ERK pathways
Creators: Narimasa Takayama - Kurume University
Hisashi Kai - Kurume University
Hiroshi Kudo - Kurume University
Suguru Yasuoka - Kurume University
Takahiro Mori - Kurume University
Takahiro Anegawa - Kurume University
Mitsuhisa Koga - Kurume University
Hidemi Kajimoto - Kurume University
Yoshitaka Hirooka - Kyushu University
Tsutomu Imaizumi - Kurume University
Resource Type: Journal article
Publication Details: Hypertension research, Vol.34(3), pp.341-347
DOI: 10.1038/hr.2010.229
PMID: 21124329
NLM abbreviation: Hypertens Res
ISSN: 0916-9636
eISSN: 1348-4214
Language: English
Date published: 03/01/2011
Academic Unit: Cardiology; Stead Family Department of Pediatrics
Record Identifier: 9984961028202771

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