| First Author | Carrillo-Sepulveda MA | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 8 | Pages | e103786 |
| PubMed ID | 25122005 | Mgi Jnum | J:223150 |
| Mgi Id | MGI:5648138 | Doi | 10.1371/journal.pone.0103786 |
| Citation | Carrillo-Sepulveda MA, et al. (2014) Role of vascular smooth muscle PPARgamma in regulating AT1 receptor signaling and angiotensin II-dependent hypertension. PLoS One 9(8):e103786 |
| abstractText | Peroxisome proliferator activated receptor gamma (PPARgamma) has been reported to play a protective role in the vasculature; however, the underlying mechanisms involved are not entirely known. We previously showed that vascular smooth muscle-specific overexpression of a dominant negative human PPARgamma mutation in mice (S-P467L) leads to enhanced myogenic tone and increased angiotensin-II-dependent vasoconstriction. S-P467L mice also exhibit increased arterial blood pressure. Here we tested the hypotheses that a) mesenteric smooth muscle cells isolated from S-P467L mice exhibit enhanced angiotensin-II AT1 receptor signaling, and b) the increased arterial pressure of S-P467L mice is angiotensin-II AT1 receptor dependent. Phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase (ERK1/2) was robustly increased in mesenteric artery smooth muscle cell cultures from S-P467L in response to angiotensin-II. The increase in ERK1/2 activation by angiotensin-II was blocked by losartan, a blocker of AT1 receptors. Angiotensin-II-induced ERK1/2 activation was also blocked by Tempol, a scavenger of reactive oxygen species, and correlated with increased Nox4 protein expression. To investigate whether endogenous renin-angiotensin system activity contributes to the elevated arterial pressure in S-P467L, non-transgenic and S-P467L mice were treated with the AT1 receptor blocker, losartan (30 mg/kg per day), for 14-days and arterial pressure was assessed by radiotelemetry. At baseline S-P467L mice showed a significant increase of systolic arterial pressure (142.0 +/- 10.2 vs 129.1 +/- 3.0 mmHg, p<0.05). Treatment with losartan lowered systolic arterial pressure in S-P467L (132.2 +/- 6.9 mmHg) to a level similar to untreated non-transgenic mice. Losartan also lowered arterial pressure in non-transgenic (113.0 +/- 3.9 mmHg) mice, such that there was no difference in the losartan-induced depressor response between groups (-13.53 +/- 1.39 in S-P467L vs -16.16 +/- 3.14 mmHg in non-transgenic). Our results suggest that interference with PPARgamma in smooth muscle: a) causes enhanced angiotensin-II AT1 receptor-mediated ERK1/2 activation in resistance vessels, b) and may elevate arterial pressure through both angiotensin-II AT1 receptor-dependent and -independent mechanisms. |
