Key result
In male Sprague-Dawley rats, AT1 receptor blockade with losartan normalized angiotensin II-induced cardiac apoptosis, bax expression, and caspase 3 activity.
Why the study?
Does AT1 receptor blockade with losartan prevent cardiac apoptosis in an in vivo rat model of angiotensin II-induced hypertension?
Does AT1 receptor blockade with losartan prevent cardiac apoptosis in an in vivo rat model of angiotensin II-induced hypertension?
In vivo AT1 receptor blockade with losartan prevents angiotensin II-induced cardiomyocyte apoptosis, demonstrating that this process is mediated by Bax and caspase 3 signaling pathways.
Answers are grounded in this paper and cite their sources.
Supports AT1 blockade attenuating cardiac apoptosis in rat models; hypothesis-generating for human hypertension translation.
Angiotensin II (ANG II) via AT(1) receptors induces apoptosis in cardiomyocytes in vitro. We tested the hypothesis that in vivo AT(1) receptor stimulation is accompanied by cardiac apoptosis and attempted to elucidate the molecular mechanisms involved in the death signaling pathway. Male Sprague-Dawley rats received ANG II (120 ng x kg(-1) x min(-1) sc) for 7 days with or without the AT(1) receptor antagonist losartan (10 mg x kg(-1) x day(-1) orally). Cardiac function was assessed by echocardiography. Apoptosis in the heart was detected and quantified by in situ TdT-mediated dUTP nick-end labeling (TUNEL) and radiolabeled DNA laddering. Expression of bax, bcl-2, caspase 3, and AT(1) and AT(2) receptors was examined by Western blot analysis. Activity of caspase 3 was also measured by a fluorometric immunosorbent enzyme assay. Tail cuff systolic blood pressure was elevated (P < 0.01, n = 6) in ANG II-infused rats (173 +/- 3 mmHg) versus controls (111 +/- 2 mmHg) and reduced by losartan (134 +/- 4 mmHg). Cardiac function was essentially unchanged in ANG II-infused rats. Increased internucleosomal DNA cleavage by TUNEL assay and radiolabeled DNA laddering showed results compatible with enhanced cardiomyocyte apoptosis in the hearts of ANG-II infused rats. The bax-to-bcl-2 ratio, expression of the active form of caspase 3 (17 kDa), and activity of caspase 3 in the hearts of the ANG II group increased more than twofold above controls. Protein expression of AT(1) and AT(2) receptors was significantly increased in ANG II-infused rats compared with control rats. Losartan-treated ANG II-infused rats exhibited normalized apoptosis, bax, caspase 3 activity, and AT(1) receptors. ANG II stimulation of AT(1) receptors in the heart in vivo is associated with an increased rate of apoptosis without major hemodynamic consequences. Bax and caspase 3 are involved in the apoptotic signaling pathway in this experimental paradigm.
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Diep et al. (2002) studied Angiotensin II-induced hypertension and cardiac apoptosis. Losartan vs. Angiotensin II alone and untreated controls was evaluated on Cardiac apoptosis, bax-to-bcl-2 ratio, and caspase 3 activity. In male Sprague-Dawley rats, AT1 receptor blockade with losartan normalized angiotensin II-induced cardiac apoptosis, bax expression, and caspase 3 activity.
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