Caveolin-3 knock-out mice develop a progressive cardiomyopathy and show hyperactivation of the p42/44 MAPK cascade

被引:226
作者
Woodman, SE
Park, DS
Cohen, AW
Cheung, MWC
Chandra, M
Shirani, J
Tang, BY
Jelicks, LA
Kitsis, RN
Christ, GJ
Factor, SM
Tanowitz, HB
Lisanti, MP
机构
[1] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
[2] Albert Einstein Coll Med, Div Hormone Dependent Tumor Biol, Bronx, NY 10461 USA
[3] Albert Einstein Coll Med, Dept Med, Div Cardiol, Bronx, NY 10461 USA
[4] Albert Einstein Coll Med, Dept Med, Div Infect Dis, Bronx, NY 10461 USA
[5] Montefiore Med Ctr, Bronx, NY 10461 USA
[6] Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA
[7] Albert Einstein Coll Med, Inst Smooth Muscle Biol, Dept Urol, Bronx, NY 10461 USA
[8] Albert Einstein Coll Med, Inst Smooth Muscle Biol, Dept Physiol, Bronx, NY 10461 USA
[9] Albert Einstein Coll Med, Inst Smooth Muscle Biol, Dept Biophys, Bronx, NY 10461 USA
[10] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA
关键词
D O I
10.1074/jbc.M205511200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A growing body of evidence suggests that muscle cell caveolae may function as specialized membrane microdomains in which the dystrophin-glycoprotein complex and cellular signaling molecules reside. Caveolin-3 (Cav-3) is the only caveolin family member expressed in striated muscle cell types (cardiac and skeletal). Interestingly, skeletal muscle fibers from Cav-3 (-/-) knockout mice show a number of myopathic changes, consistent with a mild-to-moderate muscular dystrophy phenotype. However, it remains unknown whether a loss of Cav-3 affects the phenotypic behavior cardiac myocytes in vivo. Here, we present a detailed characterization of the hearts of Cav-3 knock-out mice. We show that these mice develop a progressive cardiomyopathic phenotype. At four months of age, Cav-3 knock-out hearts display significant hypertrophy, dilation, and reduced fractional shortening, as revealed by gated cardiac MRI and transthoracic echocardiography. Histological analysis reveals marked cardiac myocyte hypertrophy, with accompanying cellular infiltrates and progressive interstitial/peri-vascular fibrosis. Interestingly, loss of Cav-3 expression in the heart does not change the expression or the membrane association of the dystrophin-glycoprotein (DG) complex. However, a marker of the DG complex, alpha-sarcoglycan, was specifically excluded from lipid raft domains in the absence of Cav-3. Because activation of the Ras-p42/44 MAPK pathway in cardiac myocytes can drive cardiac hypertrophy, we next assessed the activation state of this pathway using a phospho-specific antibody probe. We show that p42/44 MAPK (ERK1/2) is hyperactivated in hearts derived from Cav-3 knock-out mice. These results are consistent with previous in vitro data demonstrating that caveolins may function as negative regulators of the p42/44 MAPK cascade. Taken together, our data argue that loss of Cav-3 expression is sufficient to induce a molecular program leading to cardiac myocyte hypertrophy and cardiomyopathy.
引用
收藏
页码:38988 / 38997
页数:10
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