The adverse cardiopulmonary phenotype of caveolin-1 deficient mice is mediated by a dysfunctional endothelium

Journal of Molecular and Cellular Cardiology
Carsten WunderlichRuth H Strasser

Abstract

Recently generated caveolin-1 deficient mice (cav-1(-/-)) display several physiological alterations such as severe heart failure and lung fibrosis. The molecular mechanisms how the loss of caveolin-1 (cav-1) mediates these alterations are currently under debate. A plethora of studies support a role of cav-1 as a negative regulator of endothelial nitric oxide synthase (eNOS). Accordingly, constitutive eNOS hyperactivation was observed in cav-1(-/-). Given the hyperactivated eNOS enzyme we hypothesized that disturbed eNOS function is involved in the development of the cardiopulmonary pathologies in cav-1(-/-). The present study argues that loss of cav-1 results in enhanced eNOS activity but not in increased vascular tetrahydrobiopterin (BH(4)) levels (which acts as an essential eNOS cofactor) thereby causing a stoichiometric discordance between eNOS activity and BH(4) sufficient to cause dysfunctional eNOS signaling. The resultant oxidative stress is largely responsible for major cardiac and pulmonary defects observed in cav-1(-/-). BH(4) donation to cav-1(-/-) led to a normalized BH(4)/BH(2) ratio, to reduced oxidant stress, to substantial improvements of both systolic and diastolic heart function and to marked amelioration of t...Continue Reading

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