Cardiac fibrosis in mice lacking brain natriuretic peptide

Cardiac fibrosis, defined as a proliferation of interstitial fibroblasts an d biosynthesis of extracellular matrix components in the ventricles of the heart, is a consequence of remodeling processes initiated by pathologic eve nts associated with a variety of cardiovascular disorders, which leads to a bnormal myocardial stiffness and, ultimately, ventricular dysfunction. Brai n natriuretic peptide (BNP) is a cardiac hormone produced primarily by vent ricular myocytes, and its plasma concentrations are markedly elevated in pa tients with congestive heart failure and acute myocardial infarction. Howev er, its precise functional significance has been undefined. In this paper, we report the generation of mice with targeted disruption of BNP (Nppb(-/-) mice). We observed multifocal fibrotic lesions in the ventricles from Nppb (-/-) mice. No signs of systemic hypertension and ventricular hypertrophy a re noted in Nppb(-/-) mice. In response to ventricular pressure overload, f ocal fibrotic lesions are increased in size and number in Nppb(-/-) mice, w hereas no focal fibrotic changes are found in wild-type littermates (Nppb(/+) mice). This study establishes BNP as a cardiomyocyte-derived antifibrot ic factor in vivo and provides evidence for its role as a local regulator o f ventricular remodeling.