Abstract 366: Age-Related Myocardial Structural Changes are Associated with Early Alterations in HO-1 and COX-2 Protein Levels
Age-related myocyte hypertrophy and fibrosis lead to progressive diastolic dysfunction and worsening myocardial performance. To elucidate the molecular basis of these changes, we performed histologic and biochemical analysis of hearts from 4- (n=6), 12- (n=8), and 21-month-old (n=7) healthy male Fischer 344 rats. The heart weight increased with age, but the heart weight/body weight ratio decreased at 12 and 21 m. Histology revealed progressive increase in myocyte cross-sectional area (Fig⇓), and picrosirius red staining showed marked increase in interstitial collagen (Fig⇓) with age. Quantitative assessment of myocardial fibrosis by hydroxyproline assay revealed 56% and 98% increases at 12 and 21 m, respectively, (P<0.05 for both, Fig⇓) in myocardial collagen content compared with levels at 4 m. Western immunoblotting showed a significant increase in myocardial HO-1 levels at 12 m followed by minor decline. Interestingly, the myocardial levels of COX-2, which has been shown to exert antifibrotic effects, decreased at 12 m with partial recovery at 21 m. These observations indicate that myocyte hypertrophy and fibrosis start at a relatively young age even in the absence of cardiovascular risk factors. Importantly, these results suggest that myocyte hypertrophy may be related to an increase in HO-1 levels, and increased fibrosis may be due to a decrease in COX-2 levels. Further elucidation of signaling links between these biochemical and structural changes in the myocardium at an early age may eventually lead to prevention of age-related myocardial dysfunction.