Sex differences in the lung ACE/ACE2 balance in hypertensive rats

Area of Science:

• Cardiovascular Physiology
• Renal Physiology
• Pulmonary Medicine

Background:

• The renin-angiotensin system, involving ACE/Ang II and ACE2/Ang-(1-7) pathways, regulates blood pressure and tissue homeostasis.
• An imbalance between these pathways is linked to tissue damage in various pathological conditions.
• The role of sex and hypertension in lung ACE/ACE2 pathway balance remains incompletely understood.

Purpose of the Study:

• To investigate the hypothesis that male sex and hypertension are associated with an imbalance in lung ACE/ACE2 pathways.
• To compare ACE and ACE2 expression and activity in the lungs of male and female normotensive and hypertensive rats.
• To examine human lung ACE/ACE2 mRNA expression in relation to hypertension.

Main Methods:

• Experiments were conducted in male and female Wistar rats and spontaneously hypertensive rats (SHRs).
• Lung ACE and ACE2 gene expression, protein abundance, and activity were measured.
• Angiotensin II and Angiotensin-(1-7) concentrations were quantified.
• Human lung tissue data from the Genotype-Tissue Expression (GTEx) project was analyzed.

Main Results:

• Male SHRs exhibited reduced lung ACE2 mRNA, protein, and activity, alongside increased Ang II levels, compared to Wistar rats and female SHRs.
• Lung ACE mRNA was higher in male SHRs, but ACE protein and activity were similar across rat groups.
• Lung Ang-(1-7) was higher in female SHRs than in males.
• Hypertensive humans showed significantly higher lung ACE to ACE2 mRNA expression ratios than normotensive individuals.

Conclusions:

• Male hypertensive rats demonstrate an ACE/Ang II and ACE2/Ang-(1-7) pathway imbalance in the lungs, primarily driven by ACE2 downregulation.
• This ACE/ACE2 imbalance in the lungs of hypertensive males warrants further investigation for its potential role in exacerbating lung injury, particularly in respiratory infections like COVID-19.