Resolution of inflammation in healing myocardial infarcts.

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ABSTRACT: The proposed supplement will extend the studies of the parent grant to investigate fibroblast- specific actions of Smad1, and Smad2/3 in aging hearts. Study across the lifespan is a major priority of the NIH, and is particularly important in cardiovascular investigations, due to the high prevalence of heart disease in the elderly. The parent proposal explores effects of Smad1 vs Smad2/Smad3 signaling in reparative fibrosis. This supplement will extend these experiments in older animals to test the hypothesis that age-associated perturbations of the balance between fibroblast Smad1 and Smad2/3 signaling may be implicated in the pathogenesis of age-associated fibrosis and diastolic dysfunction. The hypothesis will be tested in 2 specific aims: Aim 1 will study the in vivo effects of fibroblast-specific Smad1, Smad2 and Smad3 signaling in aging hearts. Fibroblast-specific KOs generated in the parent grant will be used to examine effects of the Smads on age-associated fibrosis, remodeling and dysfunction.. Aim 2 will investigate the in vitro effects of Smad1 and Smad2/3 knockdown on senescent cardiac fibroblast phenotype and function. siRNA KD and Cre-mediated Smad deletion approaches (used in the parent grant) will be performed in cardiac fibroblasts harvested from young and old mice. Functional assays examining fibroblast migration, proliferation and myofibroblast conversion will be performed.