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 haplotype-I and II of the hAT1R gene in a 166Kb BAC (bacterial artificial chromosome) were generated. Mice received injection of endothelin-1 (1mg/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 (50%) and larger brain infarcts (60%) 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 HO-1 (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 markers and a suppressed antioxidant defense system.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…This was associated with a protection of neurons and the blood-brain barrier, and a reduction of oxidative stress within the hippocampus (738). This finding is consistent with studies in transgenic mice overexpressing AT 1 R showing increased susceptibility to strokelike injury caused by injection of ET-1 into the striatum (426). Moreover, in the two transgenic models studied, there was a worsening of the phenotype in the model with high levels of AT 1 R expression.…”

Gene Expression Behavior of a Set of Genes in Platelet and Tissue Samples from Patients with Breast Cancer

“…It has been reported that the overexpression of ANG-1 in transgenic mice induces an increase in vascularity. Moreover, while VEGF overexpression only results in increased vascular branching, VEGF-induced vessels leak [36]. In contrast, vessels induced by ANG-1 do not leak and resist leakage induced by inflammatory agents [27].…”

Correlation Between Angiotensin Receptor Type 1 Polymorphisms and Atherosclerotic Cerebral Infarction Risk

“…In a recent study, AT1R overexpression in transgenic mice strongly suppressed antioxidant activities, while enhancing brain inflammation, OS, and abnormal vascular functionality, thus leading to an increased risk of stroke-induced damage. 10 Ceolotto et al demonstrated that AT1R is expressed in higher levels in hypertensive patients carrying the A1166C CC genotype, relative to the AA or AC genotypes. 28 We, therefore, hypothesized that the AT1R polymorphisms may affect ACI susceptibility by altering AT1R levels.…”

“… 8 , 9 Mice that overexpress AT1R suffer from enhanced inflammatory activity, oxidative stress (OS), and abnormal vascular functionality, which leads to an increased risk of stroke-induced injury. 10 Additionally, AT1R activation also triggers atherosclerotic plaque vulnerability via modulation of the cholesterol metabolism. 11 …”