Abstract
About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC50) of 5.7±0.7 and 9.5±1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14±1.34 mN, without HSA: 13.54±2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73±2.17 mN, without HSA: 19.22±3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo.
Highlights
The renin-angiotensin-aldosterone system (RAAS) is an important regulator of blood pressure and salt-water homeostasis [1]
angiotensin-converting enzyme (ACE) activity was calculated by the equation: activity = 2(S/k)*D, where S is the rate of observed decrease in optical density (1/min), k is the change in optical density upon the complete cleavage of 1 mmol of FAPGG, and D is the dilution of the serum
The existence of endogenous ACE inhibitors were hypothesized before our work and being proven in our accompanying paper [23]
Summary
The renin-angiotensin-aldosterone system (RAAS) is an important regulator of blood pressure and salt-water homeostasis [1]. One of the elements of this system is the angiontensin converting enzyme. It is a zinc-metalloendodipeptidase which catalyzes the cleavage of angiotensin I to angiotensin II, and the metabolism of other peptides such as bradykinin [2]. ACE has two isoenzymes: a somatic and a testicular form [3]. Inhibition of ACE is beneficial in cardiovascular diseases [6,7,8]. ACE inhibitors are an important components of a hypothetical polypill proposed to reduce cardiovascular disease by 80% [15]. Importance of ACE inhibition may be highlighted by the fact that there are almost 47,000 hits in the Medline for ‘‘ACE inhibitor’’. The vast majority of these articles are presenting various features of exogenous ACE inhibition in animal models and clinical trials
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