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Cardioprotective effects of pitavastatin on cardiac performance and remodeling in failing rat hearts.

Abstract：

BACKGROUND:Activation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling by statins increases the activity of endothelial nitric oxide synthase (eNOS). We investigate whether statins (pitavastatin) improve cardiac function and remodeling via eNOS production associated with the PI3K-Akt signaling pathway, Rho-kinase (ROCK) pathway, and the development of oxidative stress in Dahl salt-sensitive (DS) hypertensive rats with heart failure (DSHF). METHODS:Pitavastatin (3 mg/kg per day), or pitavastatin plus specific PI3K inhibitor, wortmannin (1 mg/kg per day), or wortmannin alone were administered from the age of 11-18 weeks. Age-matched male Dahl salt-resistant (DR) rats served as a control group. RESULTS:Decreased end-systolic elastance (Ees) and percent fractional shortening (%FS) in failing rats was significantly ameliorated by pitavastatin, but not pitavastatin plus wortmannin or wortmannin alone. Upregulation of eNOS and Akt phosphorylation by pitavastatin was suppressed by pitavastatin plus wortmannin or wortmannin alone. Pitavastatin effectively inhibited the vascular lesion formation such as medial thickness and perivascular fibrosis, but not pitavastatin plus wortmannin or wortmannin alone. Activated RhoA and myosin light chain phosphorylation and RhoA, ROCK expression was inhibited by pitavastatin or a specific ROCK inhibitor, Y-27632, and downregulated eNOS expression and Akt phosphorylation was ameliorated by Y-27632. Increased expression of NAD(P)H oxidase subunits and activated p65 nuclear factor (NF)-kappaB, p44/p42 extracellular signal-regulated kinases and its downstream effector p90 ribosomal S6 kinase phosphorylation in failing rat hearts was inhibited by pitavastatin. CONCLUSIONS:These findings suggest that pitavastatin may improve cardiac function and remodeling via eNOS production associated with the PI3K-Akt signaling pathway, the ROCK pathway and oxidative stress.

journal_name

Am J Hypertens

journal_title

American journal of hypertension

authors

Kobayashi N,Takeshima H,Fukushima H,Koguchi W,Mamada Y,Hirata H,Machida Y,Shinoda M,Suzuki N,Yokotsuka F,Tabei K,Matsuoka H

doi

10.1038/ajh.2008.333

subject

Has Abstract

pub_date

2009-02-01 00:00:00

pages

176-82

issue

eissn

0895-7061

issn

1941-7225

pii

ajh2008333

journal_volume

pub_type

杂志文章

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Cardioprotective effects of pitavastatin on cardiac performance and remodeling in failing rat hearts.