Swimming training induced sex-specific differences in cardiac hypertrophy and blood levels of the renin-angiotensin system

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): FNS Background Exercise promotes physiological cardiac hypertrophy that is adaptive and reversible and influenced by age, genetics, sex, exercise intensity and type. The renin-angiotensin system (RAS) plays a crucial role in cardiovascular remodelling at both systemic and tissue levels. However, a significant gap exists in our understanding of sex differences in response to physical activity. Our objective is to characterise swimming-induced cardiac remodelling in female and male rats and RAS at both the cardiac tissue and systemic levels. Methods Male and female Lewis rats swam in a container filled with tap water at 32° C for 1 hour per day for 4 weeks or up to 8 weeks, respectively. Sedentary animals served as control. Echocardiography and immunostaining of RAS components, including angiotensin-converting enzyme 2 (ACE2) on cardiac sections' staining were performed. Cardiomyocyte (CM) size was measured. Cardiac RAS receptors were quantified with RT-PCR. Blood levels of Angiotensinogen, Angiotensins (Ang) were measured with Mass Spectrometry. Renin activity was calculated by the ratio Ang1/Angiotensinogen. Results After 4 weeks, an increase in ventricle diameter was shown in exercised male rats compared to the control. The cardiac hypertrophy was confirmed by increased heart/body weight (H/BW= 3x10-3±1.3x10-4vs2.5x10-3±3.10-5mg/g p<0.0001) and CM size (288±23 vs 198±1μm2 p=0.0028) associated with increased intra-CM immunostained ACE2 (AC2 area fraction: 38.5%±2.8%vs20%±5 p=0.0001). In females, ventricle diameter was unchanged, but wall thickness increased. Exercise was pursued for up to 8 weeks. At 6 and 8 weeks, echocardiography measurements remained similar as at 4 weeks. Hypertrophy was then confirmed by increased H/BW (3.2x10-3±1.7x10-4vs control:2.7x103 ±1.8x104mg/g p<0.0001) and CM size (335±47vs233±25μm2 p= 0.0019). An increased intra-CM-ACE2 was characterised by immunostaining (55.8%±6vs32.5%±6.6% p<0.0001) and confirmed by the increased ACE2 gene expression in cardiac tissue. At 4 weeks, the blood levels of RAS components were similar in trained and control males as well as renin activity. On contrary, exercised female rats showed increased blood levels of Angiotensinogen (4.2x10-4±7x10-5 vs 3x10-4±7x10-5au p=0.0288), Ang1 (2±1.9vs0.0±0.9au p=0.0151), Ang2 (1.2±1.5vs0.0±0.9au p=0.0204), and Ang1-7 (3.4±2.9vs 0.0±0.9au p=0.0058). The blood levels of these RAS compounds returned to the control levels after 6 and 8 weeks. In addition, a sex-distinct blood proteome was identified. Conclusion Our results showed a sex-distinct RAS regulation post-exercise and suggested a sex difference in the timing of adaptive responses at the system and cardiac tissue levels.