Estrogen protects against the development of salt-induced cardiac hypertrophy in heterozygous proANP gene-disrupted mice

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality in both men and women, but the incidence for women rises sharply after menopause. This has been mainly attributed in the reduction of the female sex hormone estrogen during menopause, suggesting that estrogen may have cardioprotective effects, although how estrogen exerts its cardioprotective effects is not fully understood. Moreover, the beneficial effect of estrogen on end-organ damage such as cardiac hypertrophy (CH) remains unclear. The aim of the present study was to examine the interaction between estrogen and the natriuretic peptide system (NPS) and their possible roles during the development of CH by using the proANP heterozygous atrial natriuretic peptide (ANP C/K) mouse as a model of salt-sensitive CH. Male, female ANP C/K mice, and also ovariectomized (Ovx) female ANP C/K mice treated with oil or estrogen were fed either a normal or high salt (HS) diet. After a 5-week treatment period, marked CH was noted in the male and oil-injected Ovx female ANP C/K mice treated with HS. The cardiac NPS, i.e. ANP, B-type natriuretic peptide, and natriuretic peptide receptor-A, was activated in these ANP C/K mice. Interestingly, the female and estrogen-injected Ovx female ANP C/K mice did not exhibit CH, and the cardiac NPS remained unchanged. Collectively, we provide direct evidence that estrogen has the ability to resist the induction of salt-induced CH in ANP C/K mice. Furthermore, the development of hypertrophy may be activating the cardiac NPS in an attempt to blunt these structural changes.

Emerging roles of natriuretic peptides and their receptors in pathophysiology of hypertension and cardiovascular regulation

“…In hypertrophied heart, ANP and BNP genes are overexpressed, suggesting that autocrine and/or paracrine effects of these natriuretic peptides, predominate and might serve as an endogenous protective mechanism against maladaptive pathological cardiac hypertrophy (153, 176, 183–186). Inactivation of either ANP or Npr1 gene in mice increases the cardiac mass to a great extent (139, 151, 154, 156, 176, 187–189). …”

Contribution of Estrogen to Sex Dimorphic Expression of Cardiac Natriuretic Peptide and Nitric Oxide Synthase Systems in ANP Gene-Disrupted Mice

“…This E2-induced activation of ANP was further confirmed in the rat heart [24]. Sangaralingham et al also demonstrated the involvement of the NP system in E2-mediated protection from salt-induced cardiac hypertrophy in heterozygous pro-ANP genedisrupted (ANP −/− ) mice [12]. In addition, E2 has been found to stimulate components of the NOS system, iNOS and eNOS, in the myocardium as evidenced from assessment of the effect of E2 on neonatal and adult rat cardiomyocytes [25].…”

“…Subcutaneous E2 injections delivered 100μg/100μL daily over a five-week period. This dose was based upon previously published work from our lab documenting the cardioprotective effects of E2 in ANP −/− mice treated with high dietary salt [11,12].…”

Excessive Sodium Intake Leads to Cardiovascular Disease by Promoting Sex-Specific Dysfunction of Murine Heart

“…HSD stimulates tissue remodeling of the heart and kidney (19) and induces the occurrence and development of aortic fibrosis (20). Recent studies have shown that the damage of HSD to the structure and function of organs is sex-specific (21)(22)(23). In women, HSD results in less severe damage to end organs, such as cardiac hypertrophy (CH), than in men (21).…”

“…Recent studies have shown that the damage of HSD to the structure and function of organs is sex-specific (21)(22)(23). In women, HSD results in less severe damage to end organs, such as cardiac hypertrophy (CH), than in men (21). The effect of HSD on hypertension has been recognized (24,25); however, there is a lack of understanding of the underlying mechanisms by which HSD damages heart tissue and causes cardiovascular disease in different sexes.…”