Abstract
The potent vasoconstrictor peptides, endothelin 1 (ET-1) and angiotensin II control adaptation of blood vessels to fluctuations of blood pressure. Previously we have shown that the circulating level of ET-1 is regulated through its proteolytic cleavage by secreted serine carboxypeptidase, cathepsin A (CathA). However, genetically-modified mouse expressing catalytically inactive CathA S190A mutant retained about 10–15% of the carboxypeptidase activity against ET-1 in its tissues suggesting a presence of parallel/redundant catabolic pathway(s). In the current work we provide direct evidence that the enzyme, which complements CathA action towards ET-1 is a retinoid-inducible lysosomal serine carboxypeptidase 1 (Scpep1), a CathA homolog with previously unknown biological function. We generated a mouse strain devoid of both CathA and Scpep1 activities (DD mice) and found that in response to high-salt diet and systemic injections of ET-1 these animals showed significantly increased blood pressure as compared to wild type mice or those with single deficiencies of CathA or Scpep1. We also found that the reactivity of mesenteric arteries from DD mice towards ET-1 was significantly higher than that for all other groups of mice. The DD mice had a reduced degradation rate of ET-1 in the blood whereas their cultured arterial vascular smooth muscle cells showed increased ET-1-dependent phosphorylation of myosin light chain 2. Together, our results define the biological role of mammalian serine carboxypeptidase Scpep1 and suggest that Scpep1 and CathA together participate in the control of ET-1 regulation of vascular tone and hemodynamics.
Highlights
Vascular resistance of the mammalian circulation system is tightly regulated by many endogenous agents that influence the blood volume, and diverse functions of endothelium, vascular smooth muscle and myocardium
Our results demonstrate that vasoactive peptide endothelin-1, is inactivated by two homologous enzymes, lysosomal serine carboxypeptidase, cathepsin A and lysosomal serine carboxypeptidase 1
We have developed a mutant strain of mice that do not produce both enzymes and found that these mice rapidly develop high blood pressure and show a reduced degradation rate of endothelin-1
Summary
Vascular resistance of the mammalian circulation system is tightly regulated by many endogenous agents that influence the blood volume, and diverse functions of endothelium, vascular smooth muscle and myocardium. When the balance of these agents is disturbed, persistent systemic hypertension develops. Endothelin-1 (ET-1) and angiotensin II (AII) are recognized among the most potent vasoactive regulators. Through their interaction with cell surface receptors both peptides can modulate blood pressure by contracting arteries, or by induction or suppression of vascular wall remodelling. The elevated ET-1 values have been previously observed in human vascular and cardiovascular disorders such as acute myocardial infarction, congestive heart failure, ischemia, atherosclerosis, hypercholestemia, systemic and pulmonary hypertension [3]. ET-1 deficient mice showed abnormal fetal development and haemodynamics [4], whereas the overexpression of human ET-1 in mice caused vascular remodelling and endothelial dysfunction [5,6]
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