Abstract
Objective: Inhibitors of the angiotensin converting enzyme (ACE) are the primarily chosen drugs to treat heart failure and hypertension. Moreover, an imbalance in tissue ACE/ACE2 activity is implicated in COVID-19. In the present study, we tested the relationships between circulating and tissue (lung and heart) ACE levels in men. Methods: Serum, lung (n = 91) and heart (n = 72) tissue samples were collected from Caucasian patients undergoing lung surgery or heart transplantation. ACE I/D genotype, ACE concentration and ACE activity were determined from serum and tissue samples. Clinical parameters were also recorded. Results: A protocol for ACE extraction was developed for tissue ACE measurements. Extraction of tissue-localized ACE was optimal in a 0.3% Triton-X-100 containing buffer, resulting in 260 ± 12% higher ACE activity over detergent-free conditions. SDS or higher Triton-X-100 concentrations inhibited the ACE activity. Serum ACE concentration correlated with ACE I/D genotype (II: 166 ± 143 ng/mL, n = 19, ID: 198 ± 113 ng/mL, n = 44 and DD: 258 ± 109 ng/mL, n = 28, p < 0.05) as expected. In contrast, ACE expression levels in the lung tissue were approximately the same irrespective of the ACE I/D genotype (II: 1423 ± 1276 ng/mg, ID: 1040 ± 712 ng/mg and DD: 930 ± 1273 ng/mg, p > 0.05) in the same patients (values are in median ± IQR). Moreover, no correlations were found between circulating and lung tissue ACE concentrations and activities (Spearman’s p > 0.05). In contrast, a significant correlation was identified between ACE activities in serum and heart tissues (Spearman’s Rho = 0.32, p < 0.01). Finally, ACE activities in lung and the serum were endogenously inhibited to similar degrees (i.e., to 69 ± 1% and 53 ± 2%, respectively). Conclusion: Our data suggest that circulating ACE activity correlates with left ventricular ACE, but not with lung ACE in human. More specifically, ACE activity is tightly coordinated by genotype-dependent expression, endogenous inhibition and secretion mechanisms.
Highlights
The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the fluid and salt homeostasis
Detergents (Triton-X-100, Triton-X-114 and SDS) were tested in the range of 0.06–5.0 V/V%. Application of these deterincreased the yield to approximately 250% angiotensin converting enzyme (ACE) concentration even at their lowest concentrations (Figure 1A), when compared to the buffer without detergents
It was found that additional organs, such as small intestines and kidneys, have comparable ACE expression levels to that in the lungs [24]; the conversion of angiotensin I into angiotensin II
Summary
The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the fluid and salt homeostasis. Levels of ACE expressions in kidneys and in small intestines were found to be comparable to those in the lung [16] Another important finding was the identification of an endogenous inhibitor for circulating ACE [17], which was later identified as serum albumin [18]. Tissue ACE/ACE2 balance (tissue AngII production) can be modulated by expression (affected by polymorphisms of both ACE and ACE2), by shedding and potentially by interacting proteins (endogenous inhibition, to albumin in the serum). These factors implicate a potentially complex interplay between tissue ACE/ACE2 expression and circulating ACE/ACE2 activity in contexts of both cardiovascular disease and COVID-19. There was a correlation between circulating and left ventricular ACE activity, but not between circulating and lung ACE activity/expression, suggestive for cardiac-specific secretion mechanisms contributing to circulating ACE activity
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