Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

Abstract

OBJECTIVE— Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator–activated receptor γ (PPARγ) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPARγ ligands could attenuate cardiac fibrosis. RESEARCH DESIGN AND METHODS— Wild-type cardiomyocyte- and macrophage-specific PPARγ −/− mice were infused with angiotensin II (AngII) to promote cardiac fibrosis and treated with the PPARγ ligand pioglitazone to determine the roles of cardiomyocyte and macrophage PPARγ in cardiac fibrosis. RESULTS— Cardiomyocyte-specific PPARγ −/− mice (cPPARγ −/− ) developed spontaneous cardiac hypertrophy with increased ventricular osteopontin expression and macrophage content, which were exacerbated by AngII infusion. Pioglitazone attenuated AngII-induced fibrosis, macrophage accumulation, and osteopontin expression in both wild-type and cPPARγ −/− mice but induced hypertrophy in a PPARγ-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPARγ–independent effects of pioglitazone: increased adiponectin expression and attenuation of proinflammatory macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis and the PPARγ ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPARγ −/− mice. CONCLUSIONS— We arrived at the following conclusions: 1 ) both cardiomyocyte-specific PPARγ deficiency and activation promote cardiac hypertrophy, 2 ) both cardiomyocyte and monocyte PPARγ regulate cardiac macrophage infiltration, 3 ) inflammation is a key mediator of AngII-induced cardiac fibrosis, 4 ) macrophage PPARγ activation prevents myocardial macrophage accumulation, and 5 ) PPARγ ligands attenuate AngII-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration. These observations have important implications for potential interventions to prevent cardiac fibrosis.

Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice fed a “Western-style diet” by increasing PPAR α and γ expression and reducing TC, MMP-9, and Cat S levels

“…Treatment with simvastatin prevented the cardiac hypertrophy and fibrosis with a significant increase in the mRNA and protein levels of PPAR alpha and PPAR gamma at 32 weeks and 40 weeks. The results are in accordance with the effects of statins for the prevention of cardiac hypertrophy by activating the PPAR pathway and reducing the generation of reactive oxygen species [8,9] . PPAR alpha, the predominant PPAR isoform in the heart, has been implicated in hypertrophic signaling.…”

“…The expression of PPAR alpha is significantly diminished during pressure overloadinduced hypertrophy. In addition, cardiomyocyte-specific PPAR gamma deficiency has been reported to promote cardiac hypertrophy [9] . Several biochemical changes take place in the heart during interstitial fibrosis, including changes in the levels of matrix metalloproteinases (MMPs) [10] and the lysosomal cysteine protease, cathepsin S (Cat S) [11] .…”

The Effects of a PPAR<i>&alpha;</i> Agonist on Myocardial Damage in Obese Diabetic Mice With Heart Failure

“…29) Likewise, PPARγ ligands have been reported to attenuate AngII-induced cardiac fibrosis. 30) The pathological findings of this study also showed that treated mice had a lower level of fibrosis. Further studies should therefore aim to determine whether this decrease is due to the slight activation of PPARγ or the activation of PPARα.…”

Rosiglitazone attenuates myocardial remodeling in spontaneously hypertensive rats

“…Yao et al 11 were the first to report that PPAR-g agonists could reduce myocardial fibrosis in diabetic rats. Caglayan et al 12 reported that PPAR-g agonists attenuate angiotensin II-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration. However, little is known about the role of rosiglitazone in cardiac remodeling evoked by essential hypertension.…”