title: Transgenic Mice Overexpressing Human Angiotensin I Receptor Gene Are Susceptible to Stroke Injury.
abstract: Hypertension is one of the co-morbid conditions for stroke and profoundly increases its incidence. Angiotensin II (AngII) is shown to be at the center stage in driving the renin angiotensin system via activation of angiotensin 1 receptor (AT1R). This makes the AT1R gene one of the 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 Hap-I and Hap-II of the hAT1R gene in a 166-kb bacterial artificial chromosome (BAC) were generated. Mice received injection of endothelin-1 (1 mg/ml) directly in to the striatum and were evaluated for neurologic deficit scores and sacrificed for analysis of infarct volume and mRNA levels of various proteins. Mice containing Hap-I suffered from significantly higher neurological deficits and larger brain infarcts than Hap II. Similarly, the molecular analysis of oxidant and inflammatory markers in brains of mice showed a significant increase (p < 0.05) in NOX-1 (2.3-fold), CRP (4.3-fold), and IL6 (1.9-fold) and a corresponding reduced expression of antioxidants SOD (60%) and HO1 (55%) in Hap-I mice as compared to Hap-II mice. These results suggest that increased expression of hAT1R rendered Hap-I TG mice susceptible to stroke-related pathology, possibly due to increased level of brain inflammatory and oxidative stress markers and a suppressed antioxidant defense system.
authors: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43560, USA. Sudhir.Jain@utoledo.edu.
authors: Sudhir
authors: S
authors: Jain
authors: Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA.
authors: Jatin
authors: J
authors: Tulsulkar
authors: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43560, USA.
authors: Anita
authors: A
authors: Rana
authors: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43560, USA.
authors: Ashok
authors: A
authors: Kumar
authors: Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA. zahoor.shah@utoledo.edu.
authors: Zahoor A
authors: ZA
authors: Shah
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects; D019332:Endothelin-1 / Q000633:toxicity; D006239:Haplotypes; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009247:NADH, NADPH Oxidoreductases / Q000032:analysis; D000074624:NADPH Oxidase 1; D009419:Nerve Tissue Proteins / Q000032:analysis; D018384:Oxidative Stress; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020521:Stroke / Q000235:genetics*; D000072105:Superoxide Dismutase-1 / Q000032:analysis
chemical_list: D019332:Endothelin-1; D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D044140:Receptor, Angiotensin, Type 1; D011993:Recombinant Fusion Proteins; C577686:interleukin-6, mouse; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1
keywords: Angiotensin receptor type 1; Endothelin-1; Hypertension; Ischemic stroke; Polymorphism
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