Abstract P107: Metabolic Syndrome and Human AT1R Expression in Transgenic Mice: Implications of Haplotype-dependent Transcriptional Regulation
Angiotensin II (Ang II) contributes to the pathophysiologies of cardiovascular and renal systems. Angiotensin receptor type 1 (AT1R) mediates these effects, and genetic variations that increase AT1R can increase these pathological outcomes. Physiological variables like age or pathologies like the metabolic syndrome alter the transcriptional milieu of cells and can provide for feedback activation of genes. In this regard, we have identified two haplotype blocks of single nucleotide polymorphisms (SNPs) in the hAT1R gene: haplotype II (Hap II: -810A, -713G, -214C, -153G) and I (Hap I: -810T, -713T, -214A, -153A). In clinical studies, Hap I is linked to human hypertension. We have generated transgenic mice (TG) with haplotypes-II and I of the hAT1R gene to study its regulation during metabolic syndrome (MetS). At baseline, ChIP assay shows increased RNA-Pol II binding (~1.6 fold higher) to the chromatin extracts from renal tissues of adult (4-6 months) male Hap I-TG mice with increased hAT1R expression (~6 fold higher). This was accompanied by higher baseline blood pressure in Hap I-TG mice (Hap I- 126±3 vs. Hap II- 115±4, p<0.05). To induce MetS, these mice were fed Western diet (45% Kcal from fat and carbohydrate each) for 12 wks. Change in body weight is higher (p<0.05) in Hap I (161.5 gm.) vs. Hap II (10.41.2 gm.) mice. MetS phenotype is characterized by increase in blood pressure that is significantly greater in Hap I mice (1362 vs. 1203 in Hap II). Transcription factors, p38/MAPK and STAT3, were induced by MetS to similar extent in both groups. However, MetS-induced up regulation of the hAT1R gene is significantly higher in vascular tissues of Hap I mice (≈6 fold), when compared to Hap II. Complementary experiments show increased inflammatory and redox markers in vascular tissues of Hap I mice, when compared to Hap II, during MetS; including, IL1 (2.2 fold), IL6 (1.8 fold), NOX1 (3.5 fold), VEGF (1.5 fold), and ICAM1 (14 fold). Thus, haplotype-dependent transcriptional regulation of the hAT1R gene causes increased hAT1R expression and blood pressure, in Hap I TG mice. Importantly, MetS exacerbates this differential gene-expression regulation, further increasing hAT1R and promoting a prooxidant/inflammatory milieu in mice with Hap I.
Author Disclosures: A. Rana: None. S. Jain: None. D. Eren: None. N. Sirianni: None. M. Kaw: None. A. Kumar: None.
- © 2015 by American Heart Association, Inc.