PPAR-γ in the Cardiovascular System

Peroxisome proliferator-activated receptor-γ (PPAR-γ), an essential transcriptional mediator of adipogenesis, lipid metabolism, insulin sensitivity, and glucose homeostasis, is increasingly recognized as a key player in inflammatory cells and in cardiovascular diseases (CVD) such as hypertension, cardiac hypertrophy, congestive heart failure, and atherosclerosis. PPAR-γ agonists, the thiazolidinediones (TZDs), increase insulin sensitivity, lower blood glucose, decrease circulating free fatty acids and triglycerides, lower blood pressure, reduce inflammatory markers, and reduce atherosclerosis in insulin-resistant patients and animal models. Human genetic studies on PPAR-γ have revealed that functional changes in this nuclear receptor are associated with CVD. Recent controversial clinical studies raise the question of deleterious action of PPAR-γ agonists on the cardiovascular system. These complex interactions of metabolic responsive factors and cardiovascular disease promise to be important areas of focus for the future

Direct monitoring pressure overload predicts cardiac hypertrophy in mice

Pressure overload (POL) is a classical model for studying cardiac hypertrophy, but there has been no direct measure of hemodynamics in a conscious ambulatory mouse model of POL. We used abdominal aortic constriction to produce POL and radiotelemetry to measure the blood pressure and heart rate for three weeks. The cardiac size correlated with the systolic pressure in the last week is better than other hemodynamic parameters. Cardiac fibrosis was more correlated to the cardiac size than to the systolic pressure. The expression of the cardiac genes that are typically associated with cardiac hypertrophy was correlated with both cardiac size and systolic pressure. In conclusion, the systolic pressure is the major determinant of cardiac hypertrophy in the murine POL model. In contrast, cardiac fibrosis shows the influence of other factors besides systolic pressure. The combination of the POL model with continuous direct measurements of hemodynamics represents a significant technological advance and will lead to an extended usefulness of POL methodologically.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58150/2/pm7_11_001.pd

PPAR-gamma in inflammation.

The ligand-dependent transcription factor, peroxisome proliferator activated receptor, (PPAR-gamma), is a member of the nuclear hormone receptor superfamily and a target of antidiabetic thiazolidinediones (TZDs). Initially characterized for its effects in glucose and lipid metabolism, PPAR-gamma activation has been shown to play critical roles in the inhibition of inflammatory vascular diseases such as atherosclerosis. Since PPAR-gamma agonists have receptor-independent actions, knockout studies are required to determine whether PPAR-gamma is necessary for the inhibitory effects of the PPAR-gamma agonists. Due to the pleiotropic effects of the PPAR-gamma activation, establishing which cell types are responsible for the anti-inflammatory effects observed in whole organism studies is difficult without the use of the cell-specific knockouts. To unravel the complex role of PPAR-gamma in inflammation and to begin categorizing relative contributions of PPAR-gamma activity in different cell types, we created two PPAR-gamma knockout models: pancreatic epithelial cell knockout and vascular endothelial cell knockout. These knockout models not only provided insight into the important role PPAR-gamma plays in the control of cell inflammation but also showed that TZDs act directly through PPAR-gamma in suppressing inflammation in an in vivo model of acute pancreatitis and in an in vitro models of endothelial cell inflammation. We show that PPAR-gamma in acinar cells, and not in inflammatory cells, is the target of the TZD anti-inflammatory activity in the model of acute pancreatitis. In vascular endothelial cells, PPAR-gamma is required for TZD activity and PPAR-gamma activation inhibits the function of a pro-inflammatory transcription factor NF-kappaB by decreasing the formation of functional transcriptional complexes at the promoters of NF-kappaB target genes.Ph.D.Biological SciencesMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126726/2/3276192.pd

Regulation of the ADMA-DDAH system in endothelial cells: a novel mechanism for the sterol response element binding proteins, SREBP1c and -2

Asymmetric dimethylarginine (ADMA) has been implicated in the progression of cardiovascular disease as an endogenous inhibitor of nitric oxide synthase. The regulation of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme responsible for metabolizing ADMA, is poorly understood. The transcription factor sterol response element binding protein (SREBP) is activated by statins via a reduction of membrane cholesterol content. Because the promoters of both DDAH1 and DDAH2 isoforms contain sterol response elements, we tested the hypothesis that simvastatin regulates DDAH1 and DDAH2 transcription via SREBP. In cultured endothelial cells, simvastatin increased DDAH1 mRNA expression compared with vehicle. In an ADMA loading experiment, simvastatin treatment resulted in a decrease in ADMA content, an indication of increased DDAH activity. The knockdown of SREBP1c protein led to an increase in DDAH1 mRNA expression and activity, whereas the knockdown of SREBP2 led to a decrease in DDAH1 mRNA expression. The role of SREBP2 in the activation of the DDAH1 was supported by chromatin immunoprecipitation studies demonstrating increased binding of SREBP2 to the DDAH1 promoter upon simvastatin stimulation. These data indicate that SREBP1c might act as a repressor and SREBP2 as an activator of DDAH transcription and activity. This study describes a novel mechanism of reciprocal regulation by the SREBP family members of the DDAH-ADMA system, which represents a potential link between cellular cholesterol content and endothelial dysfunction observed in cardiovascular disease

Hypotension, lipodystrophy, and insulin resistance in generalized PPARγ-deficient mice rescued from embryonic lethality

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