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Transgenic Mice Overexpressing Human Angiotensin I Receptor Gene Are Susceptible to Stroke Injury

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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.

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Sources of Funding

This study was funded in part by the Research Support: NIH grants HL081752 and HL66296 to AK and NIH grant R00AT004197 to ZAS.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43560, USA

    Sudhir Jain, Anita Rana & Ashok Kumar

  2. Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA

    Jatin Tulsulkar & Zahoor A. Shah

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  1. Sudhir Jain
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  2. Jatin Tulsulkar
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  3. Anita Rana
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  4. Ashok Kumar
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  5. Zahoor A. Shah
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Correspondence to Sudhir Jain or Zahoor A. Shah.

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Jain, S., Tulsulkar, J., Rana, A. et al. Transgenic Mice Overexpressing Human Angiotensin I Receptor Gene Are Susceptible to Stroke Injury. Mol Neurobiol 53, 1533–1539 (2016). https://doi.org/10.1007/s12035-015-9109-2

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  • DOI: https://doi.org/10.1007/s12035-015-9109-2

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