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Pioglitazone-induced reductions in atherosclerosis occur via smooth muscle cell-specific interaction with PPAR{gamma}.

ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)? agonists attenuate atherosclerosis and abdominal aortic aneurysms (AAAs). PPAR?, a nuclear receptor, is expressed on many cell types including smooth muscle cells (SMCs).To determine whether a PPAR? agonist reduces angiotensin II (Ang II)-induced atherosclerosis and AAAs via interaction with SMC-specific PPAR?.Low-density lipoprotein receptor (LDLR)(-/-) mice with SMC-specific PPAR? deficiency were developed using PPAR? floxed (PPAR?(f/f)) and SM22 Cre(+) mice. PPAR?(f/f) littermates were generated that did not express Cre (Cre(0/0)) or were hemizygous for Cre (Cre(+/0)). To assess the contribution of SMC-specific PPAR? in ligand-mediated attenuation of Ang II-induced atherosclerosis and AAAs, both male and female Cre(0/0) and Cre(+/0) mice were fed a fat-enriched diet with or without the PPAR? agonist pioglitazone (Pio) (20 mg/kg per day) for 5 weeks. After 1 week of feeding modified diets, mice were infused with Ang II (1000 ng/kg per minute) for 4 weeks. SMC-specific PPAR? deficiency or Pio administration had no effect on plasma cholesterol concentrations. Pio administration attenuated Ang II-increased systolic blood pressure equivalently in both Cre(0/0) and Cre(+/0) groups. SMC-specific PPAR? deficiency increased atherosclerosis in male mice. Pio administration reduced atherosclerosis in only the Cre(0/0) mice, but not in mice with SMC-specific PPAR? deficiency. SMC-specific PPAR? deficiency or Pio administration had no effect on Ang II-induced AAA development. Pio also did not attenuate Ang II-induced monocyte chemoattractant protein-1 production in PPAR?-deficient SMCs.Pio attenuates Ang II-induced atherosclerosis via the interaction with SMC-specific PPAR?, but has no effect on the development of AAAs.

SUBMITTER: Subramanian V

PROVIDER: S-EPMC2963621 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Pioglitazone-induced reductions in atherosclerosis occur via smooth muscle cell-specific interaction with PPAR{gamma}.

Subramanian Venkateswaran V Golledge Jonathan J Ijaz Talha T Bruemmer Dennis D Daugherty Alan A

Circulation research 20100826 8

<h4>Rationale</h4>Peroxisome proliferator-activated receptor (PPAR)γ agonists attenuate atherosclerosis and abdominal aortic aneurysms (AAAs). PPARγ, a nuclear receptor, is expressed on many cell types including smooth muscle cells (SMCs).<h4>Objective</h4>To determine whether a PPARγ agonist reduces angiotensin II (Ang II)-induced atherosclerosis and AAAs via interaction with SMC-specific PPARγ.<h4>Methods and results</h4>Low-density lipoprotein receptor (LDLR)(-/-) mice with SMC-specific PPARγ ...[more]

PMID: 20798360

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Project description:AimsVascular smooth muscle cells (SMCs) and their derivatives are key contributors to the development of atherosclerosis. However, studying changes in SMC gene expression in heterogeneous vascular tissues is challenging due to the technical limitations and high cost associated with current approaches. In this paper, we apply translating ribosome affinity purification sequencing to profile SMC-specific gene expression directly from tissue.Methods and resultsTo facilitate SMC-specific translatome analysis, we generated SMCTRAP mice, a transgenic mouse line expressing enhanced green fluorescent protein (EGFP)-tagged ribosomal protein L10a (EGFP-L10a) under the control of the SMC-specific αSMA promoter. These mice were further crossed with the atherosclerosis model Ldlr-/-, ApoB100/100 to generate SMCTRAP-AS mice and used to profile atherosclerosis-associated SMCs in thoracic aorta samples of 15-month-old SMCTRAP and SMCTRAP-AS mice. Our analysis of SMCTRAP-AS mice showed that EGFP-L10a expression was localized to SMCs in various tissues, including the aortic wall and plaque. The TRAP fraction demonstrated high enrichment of known SMC-specific genes, confirming the specificity of our approach. We identified several genes, including Cemip, Lum, Mfge8, Spp1, and Serpina3, which are known to be involved in atherosclerosis-induced gene expression. Moreover, we identified several novel genes not previously linked to SMCs in atherosclerosis, such as Anxa4, Cd276, inter-alpha-trypsin inhibitor-4 (Itih4), Myof, Pcdh11x, Rab31, Serpinb6b, Slc35e4, Slc8a3, and Spink5. Among them, we confirmed the SMC-specific expression of Itih4 in atherosclerotic lesions using immunofluorescence staining of mouse aortic roots and spatial transcriptomics of human carotid arteries. Furthermore, our more detailed analysis of Itih4 showed its link to coronary artery disease through the colocalization of genome-wide association studies, splice quantitative trait loci (QTL), and protein QTL signals.ConclusionWe generated a SMC-specific TRAP mouse line to study atherosclerosis and identified Itih4 as a novel SMC-expressed gene in atherosclerotic plaques, warranting further investigation of its putative function in extracellular matrix stability and genetic evidence of causality.

Dataset Information

Pioglitazone-induced reductions in atherosclerosis occur via smooth muscle cell-specific interaction with PPAR{gamma}.

Publications

Pioglitazone-induced reductions in atherosclerosis occur via smooth muscle cell-specific interaction with PPAR{gamma}.

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