Myocardial Osteopontin Expression is Associated with Collagen Fibrillogenesis in Human Dilated Cardiomyopathy

Abstract

BACKGROUND: Osteopontin (OPN), an extracellular matrix (ECM) protein, plays an important role in myocardial remodeling by promoting collagen synthesis and accumulation in experimental animal models. AIMS: We hypothesized that OPN could be expressed in myocardial tissues and contribute to collagen accumulation and myocardial dysfunction in human dilated cardiomyopathy (DCM). METHODS AND RESULTS: Endomyocardial biopsy tissues were obtained from 51 patients with DCM and 15 controls by right ventricular endomyocardial biopsy. OPN, collagen types I (Col I) and III (Col III) mRNA levels were measured by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The cellular source of OPN was analyzed using immunohistochemistry and in situ hybridization. Myocardial collagen volume fraction (CVF) was determined by digital planimetry. OPN, Col I and Col III mRNA levels were higher in DCM patients than in controls (P<0.01). OPN mRNA levels were positively correlated with Col I levels and CVF in DCM patients (OPN vs. Col I: r=0.60, P<0.01; OPN vs. CVF: r=0.52, P<0.001). Immunostaining of OPN was present in cardiomyocytes from DCM patients. In situ hybridization identified cardiomyocytes as the major source of OPN mRNA transcription in DCM patients. OPN and Col I mRNA levels were highly expressed in the DCM subgroup with large left ventricular (LV) end-systolic diameter (LVESD > or = 54.5 mm) or low LV ejection fraction (LVEF < 29.5%). There was a weak positive correlation between OPN mRNA levels and LV end-systolic diameter (r=0.39, P<0.01). Levels of OPN mRNA were also negatively correlated with LV ejection fraction (r=-0.43, P<0.01). CONCLUSIONS: These results suggest that OPN may play a pivotal role in the development of Col-I-induced cardiac fibrosis and dysfunction in human DCM.