Altered cardiac bradykinin metabolism in experimental diabetes caused by the variations of angiotensin-converting enzyme and other peptidases

Abstract

SymposiumSources of support in the form of grants: This study was supported by a grant from BristolMyers Squibb (to A.A.) and the Canadian Institutes of Health Research (grant to F.M. and A.A.).  2 AbstractThe peptidases angiotensin converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) mediate most of the kinin catabolism in normal cardiac tissue and are the molecular targets of inhibitory drugs that favorably influence diabetic complications. We studied the variations of those kininases in the myocardium of rats in experimental diabetes. ACE and NEP activities were significantly decreased in heart membranes 4-8 weeks post-streptozotocin (STZ) injection.However, insulin-dependent diabetes did not modify significantly bradykinin (BK) half-life (t 1/2 ) while the effect of both ACE (enalaprilat) and ACE and NEP (omapatrilat) inhibitors on BK degradation progressively decreased, which may be explained by the upregulation of other unidentified metallopeptidase(s). In vivo insulin treatment restored the activities of both ACE and NEP. ACE and NEP activities were significantly higher in hearts of young Zucker rats than in those of Sprague-Dawley rats. BK t 1/2 and the effects of peptidase inhibitors on t 1/2 varied accordingly. It is concluded that kininase activities are subjected to large and opposite variations in rat cardiac tissue in type I and II diabetes models. A number of tissue or molecular factors may determine these variations, such as remodeling of cardiac tissue, ectoenzyme shedding to the extracellular fluid and the pathologic regulation of peptidase gene expression.

A ligand-based approach to investigate the expression and function of angiotensin converting enzyme in intact human umbilical vein endothelial cells

“…Thus, it remains to be seen whether autocrine kinins can account for enalaprilat-induced signaling in these cells. Interestingly for the possible effect of diabetic states on ACE expression [1], high glucose failed to influence ACE expression in HUVECs (Fig. 9); the 24-72 h-high glucose treatment applied in the present study is a major modulator of endothelin converting enzyme-1 expression in these cells [16].…”

“…This may be relevant for inflammatory/infectious states, in which the vascular actions of kinins as mediators of inflammation may be potentiated due to loss of this major kininase. In addition, insulin-dependent diabetes models in rodents are associated with high TNFerved that, in the heart, the activity of ACE decreases in the weeks that follow induction of this pathology with streptozotocin [1]. This alteration, which is a likely result of inflammatory cytokine action in vivo, was fully reversed by insulin treatment.…”

“…A physiopathological example of ACE upregulation by such conditions may be the prediabetic state in Zucker rats where diacylglycerol, the endogenous PKC stimulant, is increased in vascular tissue, as well as the expression of several PKC isoforms [24]. This may explain the high ACE activity and low BK half-life in membranes isolated from young, prediabetic Zucker rats relative to Sprague-Dawley rats [1], and may deprive diabetic individuals from the postulated protective effects of low kinin levels in tissues.…”

“…In human umbilical vein endothelial cells (HUVECs), the transcription of the ACE gene mRNA and ACE activity are known to be stimulated by protein kinase (PK) A and PKC [30,35,36] and slightly via NO-controlled PKG [28], and repressed by the inflammatory cytokines IL-- [25,29]. It is not known whether these in vitro findings are predictive of enzyme variations of physiopathological importance, although large and opposite variations of ACE activities were recently reported in the heart membranes prepared from rats with type I and II diabetes (decreased and increased activities, respectively [1]). …”

Bradykinin inhibits hepatic gluconeogenesis in obese mice

“…15 Angiotensin-converting enzyme has an important role not only by converting angiotensin I to angiotensin II and thereby increasing blood pressure, but also by inactivating kinin peptides. This leads to an increase of kinin levels in patients treated with angiotensin-converting enzyme inhibitors, [16][17][18] which has been proposed to protect these patients against T2DM through a mechanism that has not been completely elucidated. 19 To study the involvement of BK in the pathophysiology of T2DM in the context of obesity, the main etiological cause of T2DM in humans, we studied obese ob/ob mice lacking BKB2R (obB2KO).…”