Genetic Interference With Endothelial PPAR-γ (Peroxisome Proliferator–Activated Receptor-γ) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1–7

Abstract

Pharmacological activation of peroxisome proliferator-activated receptor-γ (PPARγ) protects the vasculature. Much less is known regarding the cell specific impact of PPARγ when driven by endogenous ligands. Recently, we found that endothelial PPARγ protects against angiotensin II (Ang II)-induced endothelial dysfunction. Here, we explored that concept further examining if effects were sex-dependent along with underlying mechanisms. We studied mice expressing a human dominant negative mutation in PPARγ driven by the endothelial specific vascular cadherin promoter (E-V290M), using non-transgenic (non-Tg) littermates as controls. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of carotid arteries from non-Tg and E-V290M mice. Incubation of isolated arteries with Ang II (1 nmol/L) overnight had no effect in non-Tg, but reduced responses to acetylcholine by about 50% in male and female E-V290M mice (p<0.05). Endothelial function in E-V290M mice was restored to normal by inhibitors of superoxide (tempol), NADPH oxidase (VAS-2870), Rho kinase (Y-27632), ROCK2 (SLX-2119), NF-κB (NEMO-binding domain peptide), or IL-6 (neutralizing antibody). In addition, we hypothesized that PPARγ may influence the angiotensin 1-7 (Ang 1-7) arm of the renin-angiotensin system. In the basilar artery, dilation to Ang 1-7 was selectively reduced in E-V290M mice by >50% (p<0.05), an effect reversed by Y-27632. Thus, effects of Ang II are augmented by interference with endothelial PPARγ through sex-independent mechanisms, involving oxidant-inflammatory signaling and Rho kinase (ROCK2). The study also provides the first evidence that endothelial PPARγ interacts with Ang 1-7 responses. These critical roles for endothelial PPARγ have implications for pathophysiology and therapeutic approaches for vascular disease.

Endothelial PPARγ (Peroxisome Proliferator–Activated Receptor-γ) Is Essential for Preventing Endothelial Dysfunction With Aging

“…Activation of NADPH oxidase, a major source of superoxide in vascular cells, has been implicated in endothelial dysfunction in experimental models of aging and in arteries from aged humans. 4, 7, 8 We next examined whether treatment with an inhibitor of NADPH oxidase (VAS-2870) 14 would improve endothelial function in old E-V290M mice. Relaxation of the carotid artery to acetylcholine in old non-Tg mice was not affected by VAS-2870, but the response in old E-V290M mice was restored to normal levels by VAS-2870 (Figure 2).…”

“…We studied E-V290M mice (n=34) and non-Tg (n=33) littermates. 13, 14 Littermates were used as they provide the most rigorous control in relation to genetics and environment (intrauterine and post-birth environment) along with diet and age. Both male and female mice were studied.…”

“…To address this question, we used mice expressing a human dominant negative form of PPARγ expressed specifically in endothelial cells. 13, 14…”

The Nuclear Export and Ubiquitin-Proteasome-Dependent Degradation of PPARγ Induced By Angiotensin II

“…Accumulating evidence has proven the anti-oxidant and anti-inflammatory effects of PPARγ in diverse cells and tissues, such as brain [7], lung [8], liver [47], and intestine [48]. Consistently, the anti-inflammatory effects of PPARγ through suppression of pro-inflammatory cytokines have also been identified in both vascular endothelial cells [49][50] and bladder epithelial cells [51], though whether ECV304 cells are endothelial cells or epidermal cells is still controversial. The downregulation of PPARγ by Ang II disrupts PPARγ nuclear function, which may lead to the loss of beneficial effects of PPARγ on controlling oxidantand inflammatory-related signaling.…”

Role of PPARγ and retinol binding protein 7 in the vascular endothelium

“…In the absence of a prooxidant stressor, PPARγ seems dispensable since baseline blood pressure and vascular function are not significantly altered by disrupted endothelial PPARγ activity. However, in the presence of prooxidant stressors, such as high fat diet or angiotensin-II, PPARγ mounts a protective antioxidant response which is impaired if PPARγ is either absent (genetic deletion) or nonfunctional (mutation) (8,16,26). PPARγ may also play a role in the response to shear stress, as the beneficial effects of the weak PPARγ agonist telmisartan was blocked with a PPARγ antagonist (15).…”