Abstract
Abstract 308: Genetic Interference with Peroxisome Proliferator-Activated Receptor ? (PPAR?) in Smooth Muscle Augments Cerebrovascular Effects of Angiotensin I
Hypertension (Dallas, Tex. 1979), Vol.62(suppl_1), p.A308
09/2013
DOI: 10.1161/hyp.62.suppl_1.A308
Abstract
Angiotensin II (Ang II) plays a major role in vascular disease, including both large and small vessel disease in brain. PPARγ is a ligand-activated nuclear receptor that exerts protective effects within the vasculature. Although studies using high affinity PPARγ agonists [eg, thiazolidinediones (TZD)] suggest interactions between PPARγ and the renin-angiotensin system (RAS) exist, the importance of these interactions in the absence of TZD treatment is less clear. We examined the hypothesis that interference with PPARγ in vascular muscle would alter vascular effects of angiotensin I (Ang I) and Ang II. Ang I has little intrinsic biological activity, being functionally important only after conversion to Ang II, a key effector of the RAS. We studied pressurized cerebral arteries (resistance vessels) in vitro from transgenic mice expressing a dominant negative mutation in human PPARγ (P467L) under the control of the smooth muscle myosin heavy chain promoter (S-P467L). The approach allows cell-specific interference with normal PPARγ-dependent effects. Ang I (0.01-100 nM) produced only modest constriction in arteries from non-transgenic mice (eg, maximum reduction in diameter of 8±1% at 100 nM). In contrast, vasoconstriction to Ang I was increased ~4-fold in S-P467L mice (32±2% at 100 nM, P<0.01). Augmented vasoconstrictor responses to Ang I in S-P467L mice were abolished by losartan (1 μM, an inhibitor of AT1 receptors). Captopril [10 μM, an inhibitor of angiotensin converting enzyme (ACE) which converts Ang I to Ang II] completely blocked responses to low concentrations of Ang I, but only reduced effects of 100 nM Ang I by ~40%. In contrast to effects of Ang I, vasoconstrictor responses to Ang II (0.01-10 nM) and KCl (50 mM) were similar in non-transgenic and S-P467L mice (P>0.05). Vascular effects of Ang II in S-P467L mice were also abolished by losartan. These data provide the first evidence that interference with PPARγ in vascular muscle augments vascular effects of Ang I through apparent changes in both ACE-dependent and -independent metabolism of Ang I. Potent vascular effects of the precursor peptide following impairment of normal PPARγ function may exacerbate progression of Ang II-dependent vascular disease.
Details
- Title: Subtitle
- Abstract 308: Genetic Interference with Peroxisome Proliferator-Activated Receptor ? (PPAR?) in Smooth Muscle Augments Cerebrovascular Effects of Angiotensin I
- Creators
- Michael De Silva - University of IowaLisa Modrick - University of IowaPimonrat Ketsawatsomkron - University of IowaCurt D Sigmund - University of IowaFrank M Faraci - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.62(suppl_1), p.A308
- DOI
- 10.1161/hyp.62.suppl_1.A308
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Language
- English
- Date published
- 09/2013
- Academic Unit
- Molecular Physiology and Biophysics; Neuroscience and Pharmacology; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984304751702771
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