title: Role of vascular smooth muscle PPARγ in regulating AT1 receptor signaling and angiotensin II-dependent hypertension.
abstract: Peroxisome proliferator activated receptor γ (PPARγ) 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 PPARγ 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 PPARγ 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.
authors.affiliation: Department of Pharmacology and Roy J. and A. Lucille Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Maria Alicia
authors.initials: MA
authors.lastname: Carrillo-Sepulveda
authors.affiliation: Department of Pharmacology and Roy J. and A. Lucille Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Keen
authors.affiliation: Department of Pharmacology and Roy J. and A. Lucille Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Davis
authors.affiliation: Department of Pharmacology and Roy J. and A. Lucille Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
authors.affiliation: Department of Pharmacology and Roy J. and A. Lucille Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D047495:PPAR gamma; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3; D019808:Losartan