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Caveolin and β1-integrin coordinate angiotensinogen expression in cardiac myocytes.

Abstract：

BACKGROUND:The cardiac renin-angiotensin system (RAS) has been implicated in mediating myocyte hypertrophy and remodeling, although the biochemical mechanisms responsible for regulating the local RAS are poorly understood. Caveolin-1 (Cav-1)/Cav-3 double-knockout mice display cardiac hypertrophy, and in vitro disruption of lipid rafts/caveolae using methyl-β-cyclodextrin (MβCD) abolishes cardiac protection. METHODS:In this study, neonatal rat ventricular myocytes (NRVM) were used to determine whether lipid rafts/caveolae may be involved in the regulation of angiotensinogen (Ao) gene expression, a substrate of the RAS system. RESULTS:Treatment with MβCD caused a time-dependent upregulation of Ao gene expression, which was associated with differential regulation of mitogen-activated protein (MAP) kinases ERK1/2, p38 and JNK phosphorylation. JNK was highly phosphorylated shortly after MβCD treatment (2-30 min), whereas marked activation of ERK1/2 and p38 occurred much later (2-4h). β1D-Integrin was required for MβCD-induced activation of the MAP kinases. Pharmacologic inhibition of ERK1/2 and JNK enhanced MβCD-induced Ao gene expression, whereas p38 blockade inhibited this response. Adenovirus-mediated expression of wild-type p38α enhanced MβCD-induced Ao gene expression; conversely expression of dominant negative p38α blocked the stimulatory effects of MβCD. Expression of Cav-3 siRNA stimulated Ao gene expression, whereas overexpression of Cav-3 was inhibitory. Cav-1 and Cav-3 expression levels were found to be positively regulated by p38, but unaffected by ERK1/2 and JNK. CONCLUSION:Collectively, these studies indicate that lipid rafts/caveolae couple to Ao gene expression through a mechanism that involves β1-integrin and the differential actions of MAP kinase family members.

journal_name

Int J Cardiol

journal_title

International journal of cardiology

authors

Lal H,Verma SK,Feng H,Golden HB,Gerilechaogetu F,Nizamutdinov D,Foster DM,Glaser SS,Dostal DE

doi

10.1016/j.ijcard.2012.09.131

subject

Has Abstract

pub_date

2013-09-20 00:00:00

pages

436-45

issue

eissn

0167-5273

issn

1874-1754

pii

S0167-5273(12)01252-1

journal_volume

168

pub_type

杂志文章

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Caveolin and β1-integrin coordinate angiotensinogen expression in cardiac myocytes.