Abstract-Peroxisome proliferator-activated receptor (PPAR)-␥ is required for adipogenesis but is also found in the cardiovascular system, where it has been proposed to oppose inflammatory pathways and act as a growth suppressor. PPAR-␥ agonists, thiazolidinediones (TZDs), inhibit cardiomyocyte growth in vitro and in pressure overload models. Paradoxically, TZDs also induce cardiac hypertrophy in animal models. To directly determine the role of cardiomyocyte PPAR-␥, we have developed a cardiomyocyte-specific PPAR-␥-knockout (CM-PGKO) mouse model. CM-PGKO mice developed cardiac hypertrophy with preserved systolic cardiac function. Treatment with a TZD, rosiglitazone, induced cardiac hypertrophy in both littermate control mice and CM-PGKO mice and activated distinctly different hypertrophic pathways from CM-PGKO. CM-PGKO mice were found to have increased expression of cardiac embryonic genes (atrial natriuretic peptide and ␤-myosin heavy chain) and elevated nuclear factor B activity in the heart, effects not found by rosiglitazone treatment. Rosiglitazone increased cardiac phosphorylation of p38 mitogen-activated protein kinase independent of PPAR-␥, whereas rosiglitazone induced phosphorylation of extracellular signal-related kinase 1/2 in the heart dependent of PPAR-␥. Phosphorylation of c-Jun N-terminal kinases was not affected by rosiglitazone or CM-PGKO. Surprisingly, despite hypertrophy, Akt phosphorylation was suppressed in CM-PGKO mouse heart. These data show that cardiomyocyte PPAR-␥ suppresses cardiac growth and embryonic gene expression and inhibits nuclear factor B activity in vivo. Further, rosiglitazone causes cardiac hypertrophy at least partially independent of PPAR-␥ in cardiomyocytes and through different mechanisms from CM-PGKO. 9 The role of PPAR-␥ in suppression of growth and inflammation in the cardiovascular system has been inferred by determining the effects of its agonists, thiazolidinediones (TZDs), 10 -13 although PPAR-␥ does not always mediate the effects of TZDs. 14 -16 Although cardiac overexpression of PPAR-␣ or deletion of PPAR-␦ causes cardiac hypertrophy, 17,18 the role of PPAR-␥ in the heart has been controversial. 19 PPAR-␥ agonists inhibit mechanical stress-induced hypertrophy of cultured neonatal rat ventricular cardiomyocytes, reflecting, at least in part, inhibition of nuclear factor B (NF-B). 11 Similarly, PPAR-␥ agonists inhibit cardiac hypertrophy induced by aortic constriction in rats and mice. 10,20 Cardiac hypertrophy induced by the pressure overload is also slightly more pronounced in heterozygous PPAR-␥-deficient mice compared with wild-type controls. 10 However, TZDs increase the incidence of congestive heart failure in clinical trials, 21 and the approved dosage is limited by the dose of TZD that induces cardiac hypertrophy in mice, rats, and dogs. [22][23][24][25] At these limited doses, cardiac hypertrophy does not occur in humans. 26,27 These actions by TZDs may occur because of expanding blood volume. 21,22,25 However, an essential question is whether or n...

We rescued the embryonic lethality of global PPARγ knockout by breeding Mox2-Cre (MORE) mice with floxed PPARγ mice to inactivate PPARγ in the embryo but not in trophoblasts and created a generalized PPARγ knockout mouse model, MORE-PPARγ knockout (MORE-PGKO) mice. PPARγ inactivation caused severe lipodystrophy and insulin resistance; surprisingly, it also caused hypotension. Paradoxically, PPARγ agonists had the same effect. We showed that another mouse model of lipodystrophy was hypertensive, ruling out the lipodystrophy as a cause. Further, high salt loading did not correct the hypotension in MORE-PGKO mice. In vitro studies showed that the vasculature from MORE-PGKO mice was more sensitive to endothelial-dependent relaxation caused by muscarinic stimulation, but was not associated with changes in eNOS expression or phosphorylation. In addition, vascular smooth muscle had impaired contraction in response to α-adrenergic agents. The renin-angiotensin-aldosterone system was mildly activated, consistent with increased vascular capacitance or decreased volume. These effects are likely mechanisms contributing to the hypotension. Our results demonstrated that PPARγ is required to maintain normal adiposity and insulin sensitivity in adult mice. Surprisingly, genetic loss of PPARγ function, like activation by agonists, lowered blood pressure, likely through a mechanism involving increased vascular relaxation.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) have been recently derived and are used for basic research, cardiotoxicity assessment, and phenotypic screening. However, the hiPS-CM phenotype is dependent on their derivation, age, and culture conditions, and there is disagreement as to what constitutes a functional hiPS-CM. The aim of the present study is to characterize the temporal changes in hiPS-CM phenotype by examining five determinants of cardiomyocyte function: gene expression, ion channel functionality, calcium cycling, metabolic activity, and responsiveness to cardioactive compounds. Based on both gene expression and electrophysiological properties, at day 30 of differentiation, hiPS-CMs are immature cells that, with time in culture, progressively develop a more mature phenotype without signs of dedifferentiation. This phenotype is characterized by adult-like gene expression patterns, action potentials exhibiting ventricular atrial and nodal properties, coordinated calcium cycling and beating, suggesting the formation of a functional syncytium. Pharmacological responses to pathological (endothelin-1), physiological (IGF-1), and autonomic (isoproterenol) stimuli similar to those characteristic of isolated adult cardiac myocytes are present in maturing hiPS-CMs. In addition, thyroid hormone treatment of hiPS-CMs attenuated the fetal gene expression in favor of a more adult-like pattern. Overall, hiPS-CMs progressively acquire functionality when maintained in culture for a prolonged period of time. The description of this evolving phenotype helps to identify optimal use of hiPS-CMs for a range of research applications.