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

Margaret Nilsen,Asger Andersen,Julie Birkmose Axelsen,Margaret R Maclean,Hicham Labazi,Dianne Hillyard

doi:10.3390/biomedicines8100430

Margaret Nilsen, Asger Andersen + Show 4 more

Open Access

https://doi.org/10.3390/biomedicines8100430

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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.

Highlights

Pulmonary arterial hypertension (PAH), defined as a mean pulmonary arterial pressure of>20 mmHg at rest, is characterized by increased pulmonary vascular resistance, progressive remodeling and obstruction of distal pulmonary resistance arteries causing increased right ventricle (RV)afterload [1]
At the end of the study, the body weight was significantly higher in males compared to female rats; pulmonary trunk banding (PTB) surgery did not affect the body weight in the same sex (Table 2)
While the RV weight, RV/tibia and Fulton index (FI) were not different between the sham groups, these parameters were significantly higher in PTB males compared to PTB females (Figure 1a–c)

Summary

Introduction

Pulmonary arterial hypertension (PAH), defined as a mean pulmonary arterial pressure of>20 mmHg at rest, is characterized by increased pulmonary vascular resistance, progressive remodeling and obstruction of distal pulmonary resistance arteries causing increased right ventricle (RV)afterload [1]. Male PAH patients have significantly poorer outcomes than females, making male sex an independent predictor of worse survival in PAH [8,9,10] This sexual dichotomy in the development, pathogenesis and progression of the disease suggests a potential role of sex and sex hormones in the disease. Pulmonary artery banding was shown to increase RV fibrosis in male mice, while testosterone deprivation by castration appears to reduce RVH and improve survival in these male mice, without significantly affecting RV function and hemodynamics [13]. These studies suggest that sex/sex hormones are key factors in RV structure and function

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