Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin

Osteopontin (OPN), an extracellular matrix protein, is expressed in the myo cardium with hypertrophy and failure. We tested the hypothesis that OPN pla ys a role in left ventricular (LV) remodeling after myocardial infarction ( MI). Accordingly, OPN expression and LV structural and functional remodelin g were determined in wild-type (WT) and OPN knockout (KO) mice 4 weeks afte r MI. Northern analysis showed increased OPN expression in the infarcted re gion, peaking 3 days after MI and gradually decreasing over the next 28 day s. In the remote LV, OPN expression was biphasic, with peaks at 3 and 28 da ys. In situ hybridization and immunohistochemical analyses showed increased OPN mRNA and protein primarily in the interstitium. Infarct size, heart we ight, and survival were similar in KO and WT mice after MI (P=NS), whereas the lung wet weight/dry weight ratio was increased in the KO mice (P <0.005 versus sham-operated mice). Peak LV developed pressure was reduced to a si milar degree after MI in the KO and WT mice. The number of terminal deoxynu cleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive myoc ytes was similar in KO and WT mice after MI. In contrast, post-MI LV chambe r dilation was approximately twice as great in KO versus WT mice (P <0.001) . Myocyte length increased after MI in WT mice (P <0.001) but not in KO mic e. Electron microscopy showed increased collagen content in WT mice after M I but not in KO mice after Mi. Type I collagen content was increased approx imate to3-fold and approximate to7-fold in remote and infarcted regions, re spectively, of WT hearts after MI but not in KO hearts (P <0.01 versus WT h earts). Likewise, Northern analyses showed increased collagen I(alpha (1)) mRNA after MI in remote regions of WT hearts but not in KO hearts, Thus, in creased OPN expression plays an important role in regulating post-MI LV rem odeling, at least in part, by promoting collagen synthesis and accumulation .