Abstract 482: Transgenic Mice Containing Haplotype-I Of Human Angiotensin Receptor Type-1 Gene Are Susceptible To Stroke
Hypertension is one of the co-morbid conditions for, and profoundly increases the incidence of stroke in humans. Hypertension is polygenic in nature and its familial inheritance is regulated by single nucleotide polymorphisms (SNPs) in the genes associated with renin angiotensin aldosterone system (RAAS). Angiotensin II (AngII) is shown to be at the center stage in driving the RAAS via activation of angiotensin 1 receptor (AT1R). This makes AT1R gene one of the prime candidates whose differential regulation leads to the predisposition to disorders associated with hypertension. A haplotype block of four SNPs is represented primarily by haplotype-I, or Hap-I (TTAA), and haplotype-II, or Hap-II (AGCG), in the promoter of human AT1R (hAT1R) gene. To better understand the physiological role of these haplotypes, transgenic (TG) mice containing haplotype-I and II of the hAT1R gene in a 166Kb BAC (bacterial artificial chromosome) were generated. Our results show that 8 weeks old male transgenic mice containing Hap-I have increased brain hAT1R expression (6.5 fold) and have increased systolic blood pressure (11mmHg) as compared to the mice with Hap-II. Also, the results post PMCAO (permanent middle cerebral artery occlusion) suggest that the mice containing Hap-I suffered from significantly higher (p<0.05) neurological deficits (30% higher than Hap-II) and larger brain infarcts (26% larger than Hap-II). Similarly the molecular analysis of oxidant/inflammatory markers post PMCAO show a significant increase (p<0.05) in NOX-1 (1.85 fold up), CRP (9 fold up) and IL6 (2.8 fold up) and a corresponding reduced expression of antioxidants SOD (60% down) and HO-1 (55% down) in Hap-I mice as compared to Hap-II mice. These results suggest that increased expression of hAT1R leads to the damage associated with endothelial dysfunction and vascular remodeling, eventually rendering Hap-I TG mice susceptible to stroke related pathology.
Author Disclosures: S. Jain: None. J. Tulsulkar: None. A. Rana: None. Z. Shah: None. A. Kumar: None.
- © 2014 by American Heart Association, Inc.