The chronic blockade of angiotensin I-converting enzyme eliminates the sex differences of serum cytokine levels of spontaneously hypertensive rats

Abstract

Sex hormones modulate the action of both cytokines and the renin-angiotensin system. However, the effects of angiotensin I-converting enzyme (ACE) on the proinflammatory and anti-inflammatory cytokine levels in male and female spontaneously hypertensive rats (SHR) are unclear. We determined the relationship between ACE activity, cytokine levels and sex differences in SHR. Female (F) and male (M) SHR were divided into 4 experimental groups each (n = 7): sham + vehicle (SV), sham + enalapril (10 mg/kg body weight by gavage), castrated + vehicle, and castrated + enalapril. Treatment began 21 days after castration and continued for 30 days. Serum cytokine levels (ELISA) and ACE activity (fluorimetry) were measured. Male rats exhibited a higher serum ACE activity than female rats. Castration reduced serum ACE in males but did not affect it in females. Enalapril reduced serum ACE in all groups. IL-10 (FSV = 16.4 ± 1.1 pg/mL; MSV = 12.8 ± 1.2 pg/mL), TNF-α (FSV = 16.6 ± 1.2 pg/mL; MSV = 12.8 ± 1 pg/mL) and IL-6 (FSV = 10.3 ± 0.2 pg/mL; MSV = 7.2 ± 0.2 pg/mL) levels were higher in females than in males. Ovariectomy reduced all cytokine levels and orchiectomy reduced IL-6 but increased IL-10 concentrations in males. Castration eliminated the differences in all inflammatory cytokine levels (IL-6 and TNF-α) between males and females. Enalapril increased IL-10 in all groups and reduced IL-6 in SV rats. In conclusion, serum ACE inhibition by enalapril eliminated the sexual dimorphisms of cytokine levels in SV animals, which suggests that enalapril exerts systemic anti-inflammatory and anti-hypertensive effects.

Female Spontaneously Hypertensive Rats Have a Compensatory Increase in Renal Regulatory T Cells in Response to Elevations in Blood Pressure

“…Expanding on our previous results and consistent with a sex difference in the T cell profile of male and female SHR 13 , the current study also demonstrates that male SHR also have higher levels of the pro-inflammatory cytokines, IL-6 and IL-17, whereas females had greater numbers of kidney cells expressing the anti-inflammatory cytokine IL-10. In contrast to our findings, male SHR have been reported to have lower levels of circulating IL-6 than female SHR 30, 31 , however, the authors did not report tissue levels and the local cytokine environment of the kidney may be quite different from the circulation. Indeed, we published that male SHR have fewer circulating Th17 cells and more Tregs compared to female SHR, underscoring the importance of measuring local levels of cytokines and immune cells at the tissue level.…”

Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats

“…Much evidence supports that males have greater expression of “classical” RAS components Ang II and AT 1 , whereas females have greater expression of “non-classical” RAS components such as AT2 and Ang (1–7) [ 10 ]. Additionally, we [ 11 ] and others [ 8 , 12 ] have demonstrated differences in the effect of ACE inhibitors between males and females.…”

“…As several authors have demonstrated, testosterone and estrogen directly interact with RAS [ 3 , 26 , 27 ]. Based on the current literature, classical RAS components are more highly expressed in males and contribute to the development of hypertension [ 21 , 23 , 28 ], renal and cardiovascular injury [ 23 ], as well as changes in the immune system [ 11 ]. Conversely, females tend to express more non-classical RAS components such as Ang 1–7.…”

“…Animals with hypertension after renal injury and treated with ACE inhibitors (ACEi) showed decreased cardiac ACE and ACE2 activity and an improvement of cardiac structure [ 31 ]. Lim et al and us (previous study) demonstrated that castration reduced plasma ACE (-48%) [ 11 , 37 ]. In the present study, male castrated animals had a reduction of 43% in left ventricle-ACE activity.…”

Sex Differences in T Cells in Hypertension

“…In agreement with our findings, adoptive transfer of T cells from a female donor to male Rag -/- mice resulted in more IL-10 + cells in peripheral blood mononuclear and plasma levels of IL-10 than when the T cells were from a male donor, suggesting that T cells from females have greater potential to induce IL-10 production 86 . Serum IL-10, TNF-α, and IL-6 levels have also been reported to be higher in female SHR compared to males 94 , and we have previously published that female DOCA-salt rats have greater plasma IL-10 levels than males 25 . Estrogen has also been demonstrated to increase the production of IL-10, while progesterone decreases IL-23 secretion in human monocyte-derived dendritic cells 95 .…”