Sex Differences in Expression of Methionine Sulfoxide Reductase A in Hypothalamic Paraventricular Nucleus in Rats with Heart Failure after Myocardial Infarction

Abstract

Myocardial‐infarction (MI)‐induced heart failure (HF) leads to elevated oxidative stress and proinflammatory cytokine (PIC) expression in the brain and arginine vasopressin (AVP) secretion, contributing to sympathetic excitation and the progression of HF. We recently reported that female rats with HF following MI have less PIC and AVP expression in the hypothalamic paraventricular nucleus (PVN), a key cardiovascular‐related center of the brain that regulates sympathetic nerve activity and extracellular fluid volume. Female animals also exhibited 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 unclear. Emerging evidence reveals that methionine sulfoxide reductase A (MsrA), an intracellular enzyme that reverses protein methionine oxidation, is protective against brain oxidative stress, neuroinflammation and sympathetic excitation. Here we examined whether MsrA is expressed in the cardiovascular‐related centers of the brain and whether MsrA is altered in HF after MI in male and female rats. Male and female SD rats at ~13 weeks of age underwent MI to induce HF and were euthanized for molecular and immunofluorescent studies 4 weeks later. Age‐matched male and female rats served as controls. There were no differences between male and female rats in ischemic zone or left ventricular ejection fraction at 24 hours and at 4 weeks after MI as assessed by echocardiography. mRNA expression of MsrA in the PVN was significantly higher in female than male control rats (2.06 ± 0.25 vs 1.09 ± 0.16, p < 0.05). mRNA expression of MsrA in the PVN was not affected by HF in female rats (2.12 ± 0.46) but was significantly lower (0.43 ± 0.02, p < 0.01) in male HF rats compared with their age‐matched controls. There was no difference in mRNA expression of MsrA in brain cortex among four experimental groups. Confocal imaging revealed MsrA positive immunofluorescence in the neurons of the PVN, mainly in the magnocellular subdivision, in both male control and female control rats. MsrA positive immunofluorescence was also observed in the subfornical organ, another cardiovascular‐related nucleus, and in the cortex in both male control and female control rats. These results indicate that MsrA is expressed in key cardiovascular‐related centers of the brain, and that there are sex differences in the expression of MsrA in the PVN under physiological conditions and in MI‐induced HF. Whether differences in the expression of MsrA in the PVN play a role in the sex differences in the central and peripheral manifestations of MI‐induced HF deserves further investigation.Support or Funding InformationSupported by NIH grants R01HL073986 and R01HL139521This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.