Sex-Dependent Changes in Right Ventricular Gene Expression in Response to Pressure Overload in a Rat Model of Pulmonary Trunk Banding

Abstract

Right ventricular hypertrophy (RVH) and subsequent failure are consequences of pulmonary arterial hypertension (PAH). While females are four times more likely to develop PAH, male patients have poorer survival even with treatment, suggesting a sex-dependent dimorphism in right ventricular (RV) hypertrophy/compensation. This may result from differential gene expression in the RV in male vs. female. To date, the sex dependent effect of pressure overload on RV function and changes in gene expression is still unclear. We hypothesize that pressure overload promotes gene expression changes in the RV that may contribute to a poorer outcome in males vs. females. To test this hypothesis, male and female Wistar rats underwent either a sham procedure (sham controls) or moderate pulmonary trunk banding (PTB) (a model of pressure overload induced compensated RV hypertrophy) surgery. Seven weeks post-surgery, RV function was assessed in vivo, and tissue samples were collected for gene expression using qPCR. Compared to sham controls, PTB induced significant increases in the right ventricular systolic pressure, the filling pressure and contractility, which were similar between male and female rats. PTB resulted in an increase in RVH indexes (RV weight, RV weight/tibia length and Fulton index) in both male and female groups. However, RVH indexes were significantly higher in male-PTB when compared to female-PTB rats. Whilst end of procedure body weight was greater in male rats, end of procedure pulmonary artery (PA) diameters were the same in both males and females. RV gene expression analysis revealed that the following genes were increased in PTB-male rats compared with the sham-operated controls: natriuretic peptide A (ANP) and B (BNP), as well as the markers of fibrosis; collagen type I and III. In females, only BNP was significantly increased in the RV when compared to the sham-operated female rats. Furthermore, ANP, BNP and collagen III were significantly higher in the RV from PTB-males when compared to RV from PTB-female rats. Our data suggest that pressure overload-mediated changes in gene expression in the RV from male rats may worsen RVH and increase the susceptibility of males to a poorer outcome when compared to females.

Sex and gender in pulmonary arterial hypertension

“…The RV-PA uncoupling, as measured by a reduced E es /E a (<0.8; normal ratio ranging between 1.5 and 2), has been shown to be a predictor of clinical worsening and deterioration, and correlated with a significant reduction in RV ejection fraction (RVEF) [108,109]. LABAZI et al [110] have recently hypothesised that pressure overload obtained by pulmonary trunk binding (PTB) leads to gene expression changes in the RV. This study shows that RV hypertrophy indices are significantly higher in male PTB rats than females with elevated natriuretic peptide A and B as well as collagen III, increasing the susceptibility to poorer outcome in males.…”

Vanillic Acid Alleviates Right Ventricular Function in Rats With MCT-Induced Pulmonary Arterial Hypertension

“…However, the specific evidence needs to be verified with the pulmonary artery ligature technique. 29…”

“…Although animal models of pulmonary hypertension and pressure loading are important for studying the pathophysiology of RV, PAH pathology models cannot be used to study the right ventricular response independent from pulmonary vascular effects. 29,39 Protecting the structure and function of the right ventricle by reducing afterload or by acting directly on the myocardium is a key target for the treatment of pulmonary hypertension. The real answer to whether or not it acts directly on the myocardium alone needs to be demonstrated with pulmonary artery ligation experiments.…”

“…The real answer to whether or not it acts directly on the myocardium alone needs to be demonstrated with pulmonary artery ligation experiments. 1,29 Studies have shown that VA has a protective impact on RV function by inhibiting the ROCK signaling pathway and the signaling molecules that it produces downstream. VA’s suppression of the ROCK signaling pathway may prevent cardiac fibrosis, promote cardiomyocyte enlargement, and prevent cardiomyocyte apoptosis.…”

“…However, the specific evidence needs to be verified with the pulmonary artery ligature technique. 29 RV function is commonly assessed using the EES/EA ratio in invasive pressure-volume loops, which is crucial for PAH. 30 FAC (%), TAPSE/PASP, FAC/mPAP, and PASP/ESA ratios based on echocardiographic data were also found to be useful indices for evaluating RV function.…”