Abstract 219: Vascular PTH1R Signaling Limits Aortic Collagen Deposition in Diabetic LDLR-/- Mice
| Autor: | Bindu Ramachandran, Dwight A. Towler, Su-Li Cheng, Kapil Kapoor, Megan Mead, Abraham Behrmann, Henry M. Kronenberg, Ranjan J. Perera |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 36 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | When fed a high fat diet, male LDL receptor -deficient (LDLR-/-) mice develop type 2 diabetes (T2D) with concomitant arteriosclerosis. The PTH receptor (PTH1R) is highly expressed in the vasculature. To better understand the role of PTH1R signaling in aortic disease, we generated SM22-Cre;PTH1R(fl/fl) mice (PTH1R-VKO) on the LDLR-/- background. No differences in diet-induced diabetes were observed between PTH1R-VKO and Cre-negative PTH1R(fl/fl);LDLR-/- mice (CON). As compared to CON, PTH1R-VKO mice exhibited increased aortic collagen (25.0+/-4.0 vs 15.4+/-1.0 ug collagen / mg aortic dry weight; p = 0.02; n = 9 mice/genotype) but without increased calcification. Aortic pulse wave velocity was not increased but actually decreased in PTH1R-VKO mice (3.7+/-0.3 vs. 4.6+/-0.3 m/sec, p = 0.04, n = 6/genotype). Aortic adventitial myofibroblast cultures from PTH1R-VKO elaborated more collagen in vitro (53.6 +/- 4.9 ug collagen / 250,000 cells vs. 21.7 +/- 5.0 ug collagen / 250,000 cells, p = 0.01). RT-qPCR analysis identified up regulation Col1A1, Col1A2, & Col3A1. To begin to explore the mechanisms whereby PTH1R signaling controls aortic collagen gene expression, we performed expression arrays to profile mRNAs and long noncoding RNAs (lncRNAs) in diabetic PTH1R-VKO and CON cohorts (n = 5/ genotype). A large number of genes encoding myocyte contractile functions (smoothelin-like proteins, alpha-actinins, muscle creatine kinase, ryanodine receptors) were down regulated, while genes encoding collagens and 4- prolyl hydroxylase were significantly increased. A prototypic lncRNA, H19 — initially characterized in stem cells, fetal vascular smooth muscle and neointima — was down regulated in aortas of diabetic PTH1R-VKO mice (90%; p < 0.001) Conversely, the constitutively active PTH1R transgene upregulated H19 5-fold (p < 0.05) in aortic adventitial myofibroblasts. Knockdown of H19 phenocopied actions of PTH1R-deficiency, characterized by the up regulation of Col1A1, Col1A2, and Col3A1. Thus, PTH1R signaling restricts the expression and synthesis of collagen in aortic adventitial cels, mediated in part via H19. Vascular perturbations in PTH1R signaling tone and H19 expression in the aortic adventitia may contribute to the vascular disease of T2D. |
| Databáze: | OpenAIRE |
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