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.

Keywords

• pulmonary hypertension
• pulmonary trunk banding
• right ventricular hypertrophy
• compensated right ventricular failure
• fibrosis
• sexual differences