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


CONCLUSIONS
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.
Center for Translational Medicine, Temple University, Philadelphia, PA, USA.
Hind
H
Lal
Suresh K
SK
Verma
Hao
H
Feng
Honey B
HB
Golden
Fnu
F
Gerilechaogetu
Damir
D
Nizamutdinov
Donald M
DM
Foster
Shannon S
SS
Glaser
David E
DE
Dostal
D000808:Angiotensinogen / Q000096:biosynthesis*; D000818:Animals; D000831:Animals, Newborn; D051242:Caveolin 1 / Q000096:biosynthesis; D051244:Caveolin 3 / Q000096:biosynthesis*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques / Q000379:methods; D019012:Integrin beta1 / Q000096:biosynthesis*; D021962:Membrane Microdomains / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
C495537:Cav1 protein, rat; C495549:Cav3 protein, rat; D051242:Caveolin 1; D051244:Caveolin 3; D019012:Integrin beta1; D034741:RNA, Small Interfering; D000808:Angiotensinogen