Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice

Abstract

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

Mitochondrial coupling factor 6 upregulation in hypertension-induced cardiac hypertrophy

“…CF6 increases arterial blood pressure in rats, which is consistent with the high levels of CF6 seen in the plasma of patients diagnosed with hypertension [2]. CF6 functions are believed to be mediated by CF6 binding to the plasma membrane-bound ATP synthase, ecto-F1F0 complex, resulting in proton import and acidosis, whichin turn increases activated Rac1, a member of the Rho family of GTPases [3]. CF6 has several functions: it acts as a pro-atherogenic molecule in the cardiovascular system [4], regulated by estrogen in saltsensitive hypertension and cardiac systolic dysfunction in mice [3]; it attenuates exercise-induced physiological cardiac hypertrophy by inhibiting PI3K/Akt signaling in mice [5]; it plays a crucial role in the development of insulin resistance and hypertension [6]; and it appears to be a novel molecule for the pathogenesis and treatment of stroke [7].…”

“…CF6 functions are believed to be mediated by CF6 binding to the plasma membrane-bound ATP synthase, ecto-F1F0 complex, resulting in proton import and acidosis, whichin turn increases activated Rac1, a member of the Rho family of GTPases [3]. CF6 has several functions: it acts as a pro-atherogenic molecule in the cardiovascular system [4], regulated by estrogen in saltsensitive hypertension and cardiac systolic dysfunction in mice [3]; it attenuates exercise-induced physiological cardiac hypertrophy by inhibiting PI3K/Akt signaling in mice [5]; it plays a crucial role in the development of insulin resistance and hypertension [6]; and it appears to be a novel molecule for the pathogenesis and treatment of stroke [7]. Studies have shown an elevated plasma level of CF6 in patients with essential hypertension, diabetes mellitus, end-stage renal disease, acute myocardial infarction, and coronary heart disease [8]; however, research on CF6 in spontaneously hypertensive rats (SHRs) is mainly in vascular smooth muscle cells (VSMCs) and vascular endothelial cells [9,10].…”

Role of P2X7R in the development and progression of pulmonary hypertension

“…Each value was the average of at least three consecutive measurements [22]. Prior to sacrifice of the animals, RV systolic pressure (RVSP) was transduced from the right jugular vein into the vena cava and then into the right atrium followed by the right ventricle using a 1.4 F Millar Mikro-Tip catheter transducer (Millar Instruments Inc., Houston, TX).…”

Women are different: the role of coupling factor 6 in blood pressure regulation

“…2 In this issue of Hypertension Research , Izumiyama et al . 3 show that estrogen replacement has a cardioprotective function in ovariectomized females under a high-salt diet (HSD). Furthermore, they report on the mechanism whereby coupling factor 6 (CF6) overexpression increases salt-sensitive hypertension, resulting in enhanced cardiac systolic dysfunction.…”

“…3 CF6 is a component of the intrinsic membrane domain (F0) of ATP synthase, which is considered to be essential for energy transduction. 12 Recently CF6 has been identified to have multiple extracellular roles as a circulating hormone.…”