Sex Differences in the Central and Peripheral Manifestations of Heart Failure in Rats

Abstract

Heart failure (HF) is a leading cause of morbidity and mortality for both men and women. Increased sympathetic nerve activity (SNA) is a hallmark of HF and correlates with poor prognosis. We and others have demonstrated that neuroinflammation and renin‐angiotensin system activity are elevated in the cardiovascular‐related regions of the brain in HF, contributing to SNA and the progression of HF. However, most studies that have examined these sympathoexcitatory mediators in the brain in HF have been performed in male animals. The goal of this study was to determine whether sex differences exist in neuroinflammation and renin‐angiotensin system activity in the hypothalamic paraventricular nucleus (PVN), a key cardiovascular‐related center of the brain that regulates SNA and extracellular fluid volume, in rats with HF. Male and female SD rats at ~13 weeks of age underwent coronary artery ligation (CL) to induce HF and were euthanized for anatomical and molecular studies 4 weeks later. Age‐matched male and female rats served as controls. There were no differences between male and female rats in echocardiography‐defined ischemic zone or left ventricular ejection fraction at 24 hours and at 4 weeks after CL. Female rats had lower body weight than male rats, but there was no difference in body weight between HF and control rats in either sex. At 4 weeks, lung weight was similar but right ventricular (RV) and left ventricular (LV) weights were smaller in female control than male control rats. Compared with their respective controls, male HF but not female HF rats had increases in lung weight/tibial length and RV weight/tibial length. There was no difference in LV dP/dtmax and LV end‐diastolic pressure between male and female controls. LV dP/dtmax was decreased in both male HF rats and female HF rats, but male HF rats had a lower dP/dtmax. Compared with their respective control rats, male but not female HF rats had increased LV end‐diastolic pressure. In the PVN, mRNA for tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), angiotensin receptor subtype 1a receptor (AT1aR) and estrogen receptors α and β (ER‐α, ER‐β) was similar in male and female controls. mRNA for G protein‐coupled estrogen receptor (GPER) was higher and mRNA for arginine vasopressin (AVP) was lower in female control than male control rats. Both male HF and female HF rats had increases in TNF‐α, IL‐1β, AT1aR and AVP mRNA in the PVN, compared with their respective controls, but the levels were higher in the male HF rats. ER‐α and ER‐β mRNA was decreased and GPER mRNA was unchanged in male HF and female HF rats, compared with respective controls. There was no difference in ERK1/2 activity in the PVN between male and female control rats, and ERK1/2 activity in the PVN was equally increased in both male and female HF rats. Plasma angiotensin II, AVP and norepinephrine levels were similar in male and female control rats. The plasma levels of these humoral factors were higher in HF rats in either sex, but the AVP and norepinephrine levels were greater in male HF rats. These preliminary results suggest that female rats with HF following CL have less central neural inflammation and renin‐angiotensin system activity, less peripheral sympathetic and vasopressinergic activity and less hemodynamic compromise than male HF rats with the same degree of initial ischemic cardiac injury. The mechanisms responsible for these sex differences remain to be determined.Support or Funding InformationSupported by NIH HLR01HL136149 and R01HL073986.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.