Osteopontin modulates angiotensin II- induced fibrosis in the intact murine heart
Alan R. Collins, PhD*,
Janet Schnee, MD*,
Wei Wang, MD*,
Sarah Kim, BS*,
Michael C. Fishbein, MD ,
Dennis Bruemmer, MD*,
Ronald E. Law, PhD*,
Susanne Nicholas, MD, PhD*,
Robert S. Ross, MD, FACC and
Willa A. Hsueh, MD*,*
* Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los Angeles, CaliforniaUSA
Department of Pathology, The David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
Departments of Medicine, VA Healthcare System-San Diego, and University of California at San Diego, San Diego, California, USA
Manuscript received June 26, 2003;
revised manuscript received November 13, 2003,
accepted November 14, 2003.
* Reprint requests and correspondence: Dr. Willa A. Hsueh, University of California, Los Angeles, School of Medicine, Division of Endocrinology, Diabetes and Hypertension, Warren Hall, 900 Veteran Avenue, Suite 24-130, Los Angeles, California 90095-7073, USA.
whsueh{at}mednet.ucla.edu
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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Abbreviations and Acronyms
| | AngII | = angiotensin II | | ANP | = atrial natriuretic protein | | BP | = blood pressure | | BrdU | = bromodeoxyuridine | | CARP | = cardiac ankyrin repeat protein | | ECM | = extracellular matrix | | LVH | = left ventricular hypertrophy | | OPN | = osteopontin | | OPN–/– | = osteopontin null | | PBS | = phosphate-buffered saline | | RNA | = ribonucleic acid | | TGF | = transforming growth factor | | WT | = wild type |
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