The Effect of Cigarette Smoking on the Heart in Male Mice and in Ovariectomized and Non-Ovariectomized Female Mice

Abstract

Cigarette smoking (CS) is a predominant risk factor for cardiovascular disease progression worldwide. There is ample evidence of gender-based disparities in CVDs, with premenopausal females being less susceptible to the burden, given the cardioprotective effects of the female sex hormone, estrogen. Nonetheless, no study has examined gender differences in cardiac remodeling post-CS and the role played by estrogen. Thus, in this study, we aimed at investigating the CS-induced deleterious remodeling between males and females and its correlation with estrogen activity. Therefore, age-matched C57BL/6J male and female mice were allocated into five groups as follows: control female and male groups (FCTRL and MCTRL respectively), smoking female and male groups (FCS and MCS, respectively), and an ovariectomized smoking group (FOVX). Cardiac function was assessed using 2-dimensional B-mode and M-mode echocardiography, and the heart was subjected to histological and molecular analysis two days after 8 weeks of CS exposure. The cardiovascular hemodynamic assessment revealed enhanced cardiac contractility post-CS in the ovariectomized CS females only as evidenced by a significant rise in cardiac output (CO), blood pressure (BP), stroke volume (SV), and heart rate (HR). The CS female group witnessed a considerable increase in ejection fraction and heart rate. Whereas in males, cardiac systolic function and blood pressure weren’t significantly affected with CS. At the structural and histological levels, CS was associated with increased left ventricular mass (LVM) in both FCS and FOVX groups, with no change in the MCS group. Besides, the cardiomyocytes’ cross-sectional area (CSA) showed a noticeable increase in both males and females CS groups. This increase in CSA and LVM reflects CS-induced cardiomyocyte hypertrophy. Molecularly, no inflammation was detected in all CS groups. Nevertheless, CS was associated with enhanced fibrosis and apoptosis as evidenced by the rise in the mRNA expression levels of the profibrotic markers α-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF), as well as the apoptotic regulatory genes such as Bcl-2-associated X protein/B-cell lymphoma 2 ratio (Bax/BCL2) in the CS females only. In contrast, CS in males and ovariectomized females didn’t affect these apoptotic and fibrotic pathways. In conclusion, CS females, but not males, maintained pronounced cardiac systolic function with an increased BP in ovariectomized females only, 2 days after the last CS exposure. Additionally, CS non-ovariectomized females seems more prone to CS-induced cardiac injury potentially due to the alteration of estrogen activity/metabolism in the presence of CS.