Abstract 1474: Differential Roles of Cardiomyocyte and Macrophage PPARγ in Cardiac Fibrosis
Background - Peroxisome proliferator-activated receptor γ (PPARγ) ligands, widely used as insulin-sensitizers in type 2 diabetes, repress proinflammatory gene expression, including osteopontin, in several tissues. We, therefore, hypothesized that PPARγ agonists could potentially attenuate cardiac fibrosis, since osteopontin is potentially an important contributor to the development of myocardial fibrosis.
Methods and Results - Cardiomyocyte-specific PPARγ knockout mice (cPPARγ−/−) develop spontaneous cardiac hypertrophy and increased cardiac osteopontin expression and macrophage content. Angiotensin II (AngII) infusion exacerbated all these effects. Cardiomyocytes isolated from cPPARγ−/− expressed 10-fold more osteopontin mRNA, and secreted more macrophage chemoattractant factors than WT cardiomyocytes. Surprisingly, the PPARγ ligand pioglitazone attenuated AngII-induced fibrosis, macrophage accumulation and osteopontin expression in both WT and cPPARγ−/−. It also induced hypertrophy in a PPARγ-dependent manner. We pursued two mechanisms to explain these cardiomyocyte-PPARγ-independent effects:
cardiac protection by adiponectin, since PPARγ ligands increase plasma adiponectin levels and exert some of their effects through this adipokine, and
attenuation of macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis, while the PPARγ ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression and macrophage accumulation in monocyte-specific PPARγ knockout mice.
Conclusions - These data suggest
both cardiomyocyte-specific PPARγ deficiency and ligand-activation promote cardiac hypertrophy,
both cardiomyocyte and monocyte PPARγ regulate cardiac macrophage infiltration,
inflammation is a key mediator of AngII-induced cardiac fibrosis, and
macrophage PPARγ activation prevents myocardial macrophage accumulation. These observations have important implications for potential drug interventions for prevention of cardiac fibrosis.