Novel Therapeutic Role for Dipeptidyl Peptidase III in the Treatment of Hypertension

Abstract

Abstract-Dipeptidyl peptidase III (DPP III) cleaves dipeptide residues from the N terminus of polypeptides ranging from 3 to 10 amino acids in length and is implicated in pathophysiological processes through the breakdown of certain oligopeptides or their fragments. In this study, we newly identified the biochemical properties of DPP III for angiotensin II (Ang II), which consists of 8 amino acids. DPP III quickly and effectively digested Ang II with K m = 3.7×10 −6 mol/L. In the in vivo experiments, DPP III remarkably reduced blood pressure in Ang II-infused hypertensive mice without alteration of heart rate. DPP III did not affect hemodynamics in noradrenalin-induced hypertensive mice or normotensive mice, suggesting specificity for Ang II. When DPP III was intravenously injected every other day for 4 weeks after Ang II osmotic minipump implantation in mice, Ang II-induced cardiac fibrosis and hypertrophy were significantly attenuated. This DPP III effect was at least similar to that caused by an angiotensin receptor blocker candesartan. Furthermore, administration of DPP III dramatically reduced the increase in urine albumin excretion and kidney injury and inflammation markers caused by Ang II infusion. Both DPP III and candesartan administration showed slight additive inhibition in the albumin excretion. These results reveal a novel potential use of DPP III in the treatment of hypertension and its protective effects on hypertension-sensitive organs, such as the heart and kidneys.

The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

“…Recently, Dipeptidyl peptidase III (DPP III, EC 3.4.14.4) has been reported to have anti-hypertensive, anti-cardiac hypertrophic and anti-fibrotic effects in mice [46]. DPP III is zine-dependent aminopeptidase and acts to preferentially cleave two amino acids (dipeptide residues) from the N-terminus of the oligopeptides in the serum, placenta, liver and brain [46,216–218].…”

“…Recently, a number of new enzyme(s) and peptides have been reported to possess the vasodepressor properties, which may have novel therapeutic implications in cardiovascular, hypertensive, and renal diseases. Among these newly described enzyme(s) or peptides, dipeptidyl peptidase III, or DPP III [46], alamandine [47–49], and angioprotectin [50,51], have been described as “new members” of the RAS or associated with the vasoprotective arms of the RAS. These enzyme(s) or peptides act to counter or opposing the actions of ANG II and may have a potential therapeutic role in treating hypertension associated with the activation of RAS [46–48].…”

On Endogenous Angiotensin II Antagonism in Hypertension

“…In this issue Pang et al, 1 in an elegant proof of concept study in mice, have shown that DPP III administered during 4 weeks (3× per week by intravenous injection), through catalytic reduction of Ang II levels, significantly diminished systolic blood pressure, cardiac hypertrophy, and myocardial fibrosis induced by Ang II in an extent at least similar to the effect of the angiotensin receptor blocker candesartan in effective antihypertensive doses. In the same experiments, they observed that DPP III diminished urine albumin excretion, kidney damage, and the renal protein levels of the pro inflammatory molecule monocyte chemoattractant protein-1 and the procoagulant platelet activator inhibitor-1.…”

“…In this issue of Hypertension, the role of dipeptidyl peptidase III (DPP III) as a new antihypertensive candidate has been characterized in the mice. 1 Similar to DPP III, the carboxy peptidase ACE2 mediates degradation from Ang II to Ang (1-7) and also from Ang I to Ang (1)(2)(3)(4)(5)(6)(7)(8)(9). Both peptides contribute to the antihypertensive/ vasoprotective effects of the counterregulatory RAAS pathway ( Figure).…”

“…In the same experiments, they observed that DPP III diminished urine albumin excretion, kidney damage, and the renal protein levels of the pro inflammatory molecule monocyte chemoattractant protein-1 and the procoagulant platelet activator inhibitor-1. The focus of this study 1 was on the capability of DPP III to hydrolize Ang II, the main effector of the RAAS. In addition, this enzyme is able to hydrolyze Ang IV implicated in hypertrophy, the nuclear factor kappa-light-chain-enhancer of activated B cells activation and also in increased levels of platelet activator inhibitor-1, monocyte chemoattractant protein-1, interleukin-6, and tumor necrosis factor-α.…”