Background-We reported that phospholipase C (PLC)-␦1 activity was enhanced 3-fold in patients with coronary spastic angina. We detected variant PLC-␦1 with replacement of arginine 257 by histidine (R257H) showing increased enzymatic activity. We tested the hypothesis that increased PLC-␦1 activity causes enhanced coronary vasomotility. Methods and Results-We generated transgenic (TG) mice with human R257H variant PLC-␦1 in vascular smooth muscle cells. PLC enzymatic activity in the coronary artery was increased by 2.57 and 1.89 times, respectively, in homozygous and heterozygous TG compared with wild-type (WT) mice. ST elevation after ergometrine occurred in 17 of 18 homozygous TG, 6 of 20 heterozygous TG, and 3 of 22 WT mice (PϽ0.01, homozygous TG versus WT; PϽ0.05, homozygous TG versus heterozygous TG; PϭNS, heterozygous TG versus WT). ST elevation was associated with bradyarrhythmias in homozygous TG mice. Focal coronary artery narrowing was documented with the microvascular filling technique in 3 of 5 homozygous TG mice after ergometrine but not in any of 7 WT mice (PϽ0.05). In the isolated Langendorff hearts, coronary perfusion pressure was increased after ergometrine in homozygous TG mice (PϽ0.01) but not in heterozygous TG or WT mice. Coronary perfusion pressure increase after prostaglandin F 2␣ was similar among homozygous TG, heterozygous TG, and WT mice. Cultured rat aortic smooth muscle cells transfected with variant PLC-␦1 showed a higher PLC activity than those with WT PLC-␦1 (PϽ0.05) and furthermore showed greater intracellular Ca 2ϩ response to acetylcholine in variant than in WT PLC-␦1 (PϽ0.05). Conclusions-Increased PLC-␦1 activity enhances coronary vasomotility such as that seen in patients with coronary spastic angina.
In male coupling factor 6 (CF6)-overexpressing transgenic (TG) mice, a high-salt diet induces hypertension and cardiac systolic dysfunction with excessive reactive oxygen species generation. However, the role of gender in CF6-mediated pathophysiology is unknown. We investigated the effects of ovariectomy and estrogen replacement on hypertension, cardiac dysfunction and Rac1 activity, which activates radical generation and the mineralocorticoid receptor, in female TG mice. Fifteen-week-old male and female TG and wild-type (WT) mice were fed a normal-or high-salt diet for 60 weeks. Systolic and diastolic blood pressures were higher in the TG mice fed a high-salt diet than in those fed a normal-salt diet at 20-60 weeks in males but only at 60 weeks in females. The blood pressure elevation under high-salt diet conditions was concomitant with a decrease in left ventricular fractional shortening. In the WT mice, neither blood pressure nor cardiac systolic function was influenced by a high-salt diet. In the female TG mice, bilateral ovariectomy induced hypertension with cardiac systolic dysfunction 8 weeks after the initiation of a high-salt diet. The ratios of Rac1 bound to guanosine triphosphate (Rac1-GTP) to total Rac1 in the heart and kidneys were increased in the ovariectomized TG mice, and estrogen replacement abolished the CF6-mediated pathophysiology induced under the high-salt diet conditions. The overexpression of CF6 induced salt-sensitive hypertension, complicated by systolic cardiac dysfunction, but its onset was delayed in females. Estrogen has an important role in the regulation of CF6-mediated pathophysiology, presumably via the downregulation of Rac1. Hypertension Research (2012) 35, 539-546; doi:10.1038/hr.2011.232; published online 19 January 2012Keywords: coupling factor 6; estrogen; heart failure; hypertension; salt INTRODUCTION Premenopausal women have a lower risk and incidence of hypertension and cardiovascular disease than age-matched men. However, this gender advantage gradually disappears after menopause. Although blood pressure is lower in premenopausal women than in men, after menopause, it increases to levels similar to or higher than those of agematched men. 1,2 The recent Nurse's Health Study 3 and WISE Study, 4 as well as others, 5 have demonstrated that compared with women with normal endogenous estrogen levels, young women undergoing early menopause owing to ovarian dysfunction or bilateral ovariectomy have an increased risk of cardiovascular disease. In animal models of cardiovascular disease, females exhibited lower mortality, less vascular injury, better preservation of cardiovascular function, and slower progression to decompensated heart failure than did males, although such differences were abolished after ovariectomy or induction of a deficiency in endogenous estrogen. 6,7-9 These findings clearly suggest that sex hormones have a cardioprotective role in women. Although randomized, prospective, primary or secondary prevention trials failed
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.