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Abstract
The angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II) and angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) (Ang-(1-7)) pathways are coexpressed in most tissues. The balance between these pathways determines, at least in part, whether tissue damage will occur in response to pathological stimuli. The present study tested the hypothesis that male sex and high blood pressure are associated with ACE/ACE2 imbalance in the lungs. Experiments were conducted in male and female Wistar rats and spontaneously hypertensive rats (SHRs). Lung ACE and ACE2 gene expression was also evaluated in normotensive and hypertensive humans using the Genotype-Tissue Expression (GTEx) project. Compared with Wistar rats and female SHRs, male SHRs displayed reduced lung ACE2 mRNA, ACE2 protein abundance and ACE2 activity, and increased Ang II concentration. Lung ACE mRNA levels were higher in male SHRs than in Wistar rats, whereas lung ACE protein abundance and activity were similar among the four groups of rats. Lung Ang-(1-7) concentration was higher in female than in male SHRs (89 ± 17 vs. 43 ± 2 pg/g, P<0.05). Lung ACE to ACE2 mRNA expression in hypertensive patients was significantly higher than that in normotensive subjects. Taken together, these results demonstrate that male hypertensive rats display imbalance between the ACE/Ang II and ACE2/Ang-(1-7) pathways in the lungs mainly attributable to ACE2 down-regulation. Further studies should be conducted to investigate whether this imbalance between ACE/ACE2 may promote and accelerate lung injury in respiratory infections, including coronavirus disease 2019 (COVID-19).
Highlights
Biological sex is recognized as a crucial determinant of susceptibility and clinical outcomes in non-communicable and infectious diseases
The main findings of our study can be summarized as follows: (i) male hypertensive rats displayed imbalance between the angiotensin-converting enzyme (ACE)/Ang angiotensin II (II) and angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7) pathways in the lungs; (ii) this renin–angiotensin system (RAS) imbalance resulted in a higher lung Angiotensin II (Ang II) concentration that is mainly attributable to decreased lung ACE2 activity since neither high blood pressure nor biological sex was associated with changes in lung enzymatic ACE function; (iii) down-regulation of lung ACE2 activity in male hypertensive rats was accompanied by decreased ACE2 protein abundance and ACE2 mRNA expression but did not seem to be dependent on increased a disintegrin and metalloprotease 17 (ADAM17)-mediated shedding; (iv) the lung ACE/ACE2 mRNA ratio was
Based on the results shown here, we suggest that down-regulation of ACE2 activity in the lungs leads to the decreased consumption of Ang II and that lower Ang-(1-7) production may be primarily due to decreased ACE2 mRNA transcription and translation
Summary
Biological sex is recognized as a crucial determinant of susceptibility and clinical outcomes in non-communicable and infectious diseases. Sex differences have been well investigated in cardiology since several epidemiological studies demonstrated that premenopausal women are less prone to developing cardiovascular disease (CVDs) than age-matched men [1,2,3]. High blood pressure, a major risk factor for CVDs, prevails in men before the age of 50 [4,5,6]. Male bias has emerged in the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sex differences have been consistently implicated in the severity of COVID-19 [7], including mortality and the need for admission to intensive care [8]. One potential mechanism responsible for sex dimorphism in hypertension and COVID-19 is the effect of sex steroid hormones on the renin–angiotensin system (RAS) [9,10]
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