Journal article
Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator-Activated Receptor-γ Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate-Salt Hypertension
Hypertension (Dallas, Tex. 1979), Vol.67(1), pp.214-222
01/2016
DOI: 10.1161/HYPERTENSIONAHA.115.06391
PMCID: PMC4679422
PMID: 26597823
Abstract
Loss of peroxisome proliferator-activated receptor-γ (PPARγ) function causes hypertension, whereas its activation lowers blood pressure. Evidence suggests that these effects may be attributable to PPARγ activity in the vasculature. However, the specific transcriptional targets of PPARγ in vessels remain largely unidentified. In this study, we examined the role of smooth muscle PPARγ during salt-sensitive hypertension and investigated its transcriptional targets and functional effect. Transgenic mice expressing dominant-negative PPARγ (S-P467L) in smooth muscle cells were more prone to deoxycorticosterone acetate-salt-induced hypertension and mesenteric arterial dysfunction compared with nontransgenic controls. Despite similar morphometry at baseline, vascular remodeling in conduit and small arteries was enhanced in S-P467L after deoxycorticosterone acetate-salt treatment. Gene expression profiling in aorta and mesenteric arteries revealed significantly decreased expression of tissue inhibitor of metalloproteinase-4 (TIMP-4) in S-P467L. Expression of TIMP-4 was increased by deoxycorticosterone acetate-salt treatment, but this increase was ablated in S-P467L. Interference with PPARγ activity either by treatment with a PPARγ inhibitor, GW9662, or by expressing P467L PPARγ markedly suppressed TIMP-4 in primary smooth muscle cells. PPARγ binds to a PPAR response element (PPRE) in chromatin close to the TIMP-4 gene in smooth muscle cells, suggesting that TIMP-4 is a novel target of PPARγ. The interference with PPARγ and decrease in TIMP-4 were accompanied by an increase in total matrix metalloproteinase activity. PPARγ-mediated loss of TIMP-4 increased, whereas overexpression of TIMP-4 decreased smooth muscle cell migration in a scratch assay. Our findings highlight a protective mechanism induced by PPARγ in deoxycorticosterone acetate-salt treatment, establishing a novel mechanistic link between PPARγ and TIMP-4.
Details
- Title: Subtitle
- Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator-Activated Receptor-γ Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate-Salt Hypertension
- Creators
- Pimonrat Ketsawatsomkron - From the Department of Pharmacology, Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Iowa City Veterans Affairs Healthcare System, IAHenry L Keen - From the Department of Pharmacology, Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Iowa City Veterans Affairs Healthcare System, IADeborah R Davis - From the Department of Pharmacology, Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Iowa City Veterans Affairs Healthcare System, IAKo-Ting Lu - From the Department of Pharmacology, Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Iowa City Veterans Affairs Healthcare System, IAMadeliene Stump - From the Department of Pharmacology, Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Iowa City Veterans Affairs Healthcare System, IAT Michael De Silva - From the Department of Pharmacology, Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Iowa City Veterans Affairs Healthcare System, IAAline M Hilzendeger - From the Department of Pharmacology, Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Iowa City Veterans Affairs Healthcare System, IAJustin L Grobe - From the Department of Pharmacology, Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Iowa City Veterans Affairs Healthcare System, IAFrank M Faraci - From the Department of Pharmacology, Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Iowa City Veterans Affairs Healthcare System, IACurt D Sigmund - From the Department of Pharmacology, Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Iowa City Veterans Affairs Healthcare System, IA. curt-sigmund@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.67(1), pp.214-222
- Publisher
- United States
- DOI
- 10.1161/HYPERTENSIONAHA.115.06391
- PMID
- 26597823
- PMCID
- PMC4679422
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Grant note
- HL084207 / NHLBI NIH HHS I01 BX001399 / BLRD VA T32 GM007337 / NIGMS NIH HHS HL113863 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS R37 HL048058 / NHLBI NIH HHS K99 HL098276 / NHLBI NIH HHS R01 HL125603 / NHLBI NIH HHS HL048058 / NHLBI NIH HHS R00 HL098276 / NHLBI NIH HHS P01 NS024621 / NINDS NIH HHS R01 HL113863 / NHLBI NIH HHS NS024621 / NINDS NIH HHS HL098276 / NHLBI NIH HHS R01 HL048058 / NHLBI NIH HHS P01 HL084207 / NHLBI NIH HHS HL125603 / NHLBI NIH HHS HL062984 / NHLBI NIH HHS
- Language
- English
- Date published
- 01/2016
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984040333202771
Metrics
19 Record Views