Pathophysiologic Implications of Angiotensin I-Converting Enzyme as a Mechanosensor: Diabetes

Abstract

If somatic angiotensin I-converting enzyme (ACE) were a mechanosensor, as recently claimed, it would provide insight into the molecular origin of most adult diseases, such as diabetes, cancer, autoimmune diseases, and psychiatric disease, as well as aging itself. The "ACE as mechanosensor" hypothesis holds that tissue ACE is activated by turbulent flow with each heart beat, so that age-dependent diseases begin with a signal from the vasculature. Activation of ACE would thus represent the first of many amplification steps ("cascades"), placing it at the origin of most age-dependent diseases. As a corollary, effective inhibition of tissue ACE might significantly delay the progression of most diseases of aging. In this paper we will explore how useful this hypothesis is in explaining the molecular pathogenesis of diabetes and its complications, in which aging is accelerated.

The Central Role of Angiotensin I-Converting Enzyme in Vertebrate Pathophysiology

“…If tACE can already sense flow and redox state, why did the gene undergo duplication, an event so successful that it was conserved in all species subsequent to the appearance of Chordata? How did sACE perhaps contribute to the Cambrian explosion [16]?…”

“…Somatic ACE (sACE), the duplicated form of the enzyme with two active sites, is a type I membrane protein like tACE. sACE anchored in the plasma membrane of endothelial cells projects minimally into the vascular lumen [16]. Besides endothelial cells, sACE is also present on epithelia exposed to high flow, such as the brush border membrane of the kidney proximal tubule, jejunal microvilli, and the choroid plexus.…”

“…Interestingly, these tissues share the unusual ability to undergo hypertrophy. Angiotensin II, the product of sACE, helps initiate compensatory renal growth [16].…”

“…Nevertheless, how sACE is activated in situ may help explain such diverse phenomena as erythropoetin production by the renal "critmeter" [73], ventilation/perfusion ("V/Q") matching in the lung [74], activation of the immune response during infection [75][76][77][78], production of myeloid cells in the bone marrow [79,80], and the vicious cycle of ischemia, thrombosis, endothelial cell apoptosis, and vascular collapse seen in conditions such as sickle cell crisis, malignant hypertension, and disseminated intravascular coagulation (DIC) [81]. In addition, sACE is an excellent candidate gene responsible for most age-related diseases as well as aging itself in all vertebrates [4,16,20,82].…”

Review of the potential health impact of β-casomorphins and related peptides

“…The half-life of certain peptides in plasma is very short, with an order of magnitude of one minute (Gardner, 1998). Angiotensin II degradation occurs even within seconds (Moskowitz, 2002(Moskowitz, , 2003. Nevertheless, peptides can also be more resistant to hydrolysis in blood, because they may be weakly bound to carrier proteins which can protect them.…”