Osteopontin modulates angiotensin II-induced fibrosis in the intact murine heart
AR Collins, J Schnee, W Wang, S Kim… - Journal of the American …, 2004 - jacc.org
AR Collins, J Schnee, W Wang, S Kim, MC Fishbein, D Bruemmer, RE Law, S Nicholas…
Journal of the American College of Cardiology, 2004•jacc.orgObjectives: Osteopontin (OPN) is upregulated in left ventricular hypertrophy and is
stimulated by angiotensin II (AngII). Our objective was to determine whether mice deficient in
OPN would be protected from AngII-induced cardiac fibrosis. Background: Interstitial fibrosis
can lead to myocardial dysfunction and ultimately heart failure. Osteopontin activates
integrins that regulate cell adhesion, migration, and growth, thus implicating OPN in the
process of cardiac fibrosis. Methods: Osteopontin null (OPN−/−) mice (n= 18) and wild-type …
stimulated by angiotensin II (AngII). Our objective was to determine whether mice deficient in
OPN would be protected from AngII-induced cardiac fibrosis. Background: Interstitial fibrosis
can lead to myocardial dysfunction and ultimately heart failure. Osteopontin activates
integrins that regulate cell adhesion, migration, and growth, thus implicating OPN in the
process of cardiac fibrosis. Methods: Osteopontin null (OPN−/−) mice (n= 18) and wild-type …
Objectives
Osteopontin (OPN) is upregulated in left ventricular hypertrophy and is stimulated by angiotensin II (AngII). Our objective was to determine whether mice deficient in OPN would be protected from AngII-induced cardiac fibrosis.
Background
Interstitial fibrosis can lead to myocardial dysfunction and ultimately heart failure. Osteopontin activates integrins that regulate cell adhesion, migration, and growth, thus implicating OPN in the process of cardiac fibrosis.
Methods
Osteopontin null (OPN−/−) mice (n = 18) and wild-type controls (n = 20) were infused with AngII (2.5 or 3.0 μg/kg/min) for four days or three weeks via osmotic mini-pumps. Hearts were assessed morphometrically and histologically, including quantitative assessment of fibrosis via optical microscopic imaging analysis. Cardiac fibroblasts derived from these mice were evaluated for adhesion and proliferation. Cardiac transcript expression for cytokines, extracellular matrix (ECM), integrin, and atrial natriuretic peptide were assessed.
Results
Osteopontin−/−mice exhibited less cardiac fibrosis (0.7%) than wild-type mice (8.0%) (p < 0.01) and lowered heart/body weight ratios (0.10% vs. 0.23%) (p < 0.01) after three weeks of AngII infusion. Expression of transforming growth factor-beta, fibronectin, and collagen was not different between OPN−/−and wild-type mice, despite the decrease in ECM accumulation in the OPN−/−mice. Adhesion to ECM substrates decreased by 30% to 50% in cardiac fibroblasts of OPN−/−mice but was restored in OPN−/−cells by the addition of recombinant osteopontin.
Conclusions
Osteopontin mediates cardiac fibrosis, probably through the modulation of cellular adhesion and proliferation. Because OPN is increased in cardiac hypertrophy and its lack attenuates fibrosis, understanding of OPN function is essential to extend our knowledge about molecular determinants of cardiac hypertrophy and failure.
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