The anti-inflammatory peptide Ac-SDKP: Synthesis, role in ACE inhibition, and its therapeutic potential in hypertension and cardiovascular diseases

Kumar, Nitin; Yin, Congcong

doi:10.1016/j.phrs.2018.07.006

Cited by 48 publications

(45 citation statements)

References 132 publications

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“…Ac-SDKP is one peptide that can be specifically hydrolyzed by the N-terminal catalytic domain of ACE between aspartyl and lysyl residues, and this peptide possesses potent antifibrotic and anti-inflammatory functions (12,17,18). Growing evidence indicates that although vasculature fibrosis can be relieved by the use of ACE inhibitors to control blood pressure, the effect is actually mediated by the increased availability of Ac-SDKP (19,20). An increasing number of studies have proven the potential application of Ac-SDKP as an antifibrotic agent in multiple organs (21,22).…”

Section: Discussionmentioning

confidence: 99%

d‐amino acid modification protects N‐Acetyl‐seryl‐aspartyl‐lysyl‐proline from physiological hydroxylation and increases its antifibrotic effects on hepatic fibrosis

et al. 2019

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N‐Acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) is a critical negative regulator of fibrosis development in the liver. However, its extremely short half‐life in vivo greatly compromises its potential applications. Here, we report an Ac‐SDKP analog peptide with d‐amino acid replacement (Ac‐SDDKDP). The stability of Ac‐SDDKDP and its prevention of liver fibrosis were investigated in vitro and in vivo. The stabilities of Ac‐SDKP and Ac‐SDDKDP exposed to angiotensin‐1‐converting enzyme (ACE) and their half‐lives in rats and human sera were determined by high‐performance liquid chromatography. The inhibitory effects of Ac‐SDKP and Ac‐SDDKDP on the proliferation and activation of hepatic stellate cells (HSC‐T6) were evaluated using the Cell Counting Kit‐8, Western blotting, reverse transcription quantitative polymerase chain reaction, and immunofluorescence assays. Finally, the protective effects of Ac‐SDKP and Ac‐SDDKDP on carbon tetrachloride (CCl4)‐induced liver fibrosis in rats were compared. d‐Amino acid replacement significantly enhanced the stability of the peptide to ACE and prolonged the half‐life of Ac‐SDKP in rats and human sera. The Ac‐SDKP‐mediated inhibition of HSC‐T6 cell proliferation was well preserved, and Ac‐SDDKDP exerted inhibitory effects comparable to Ac‐SDKP on α‐smooth muscle actin (α‐SMA), collagen I and III expression, and phosphorylated‐Smad‐2 expression. After intraperitoneal (i.p.) administration, Ac‐SDDKDP exhibited significantly greater protection than Ac‐SDKP against CCl4‐induced liver fibrosis in rats. The serum alanine aminotransferase, aspartate aminotransferase, albumin, and total protein levels of the Ac‐SDDKDP‐treated rats were significantly lower than those of the Ac‐SDKP‐treated rats. α‐SMA, CD45, and collagen I and III expression, as well as Smad‐2 phosphorylation were significantly attenuated in the livers of the Ac‐SDDKDP‐treated rats compared to those of the Ac‐SDKP‐treated rats. Furthermore, we showed that the Ac‐SDDKDP concentration in the rat liver increased to a physiological level of 60 min after i.p. administration, although i.p. administration of Ac‐SDKP failed to enhance the peptide concentration in the rat liver. Our findings indicate that d‐amino acid replacement is a simple and effective method to enhance the stability of Ac‐SDKP. Ac‐SDDKDP represents potential application of Ac‐SDKP in fibrosis treatment and provides a new potential treatment strategy for liver fibrosis. © 2019 IUBMB Life, 71(9):1302–1312, 2019

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Section: Discussionmentioning

confidence: 99%

d‐amino acid modification protects N‐Acetyl‐seryl‐aspartyl‐lysyl‐proline from physiological hydroxylation and increases its antifibrotic effects on hepatic fibrosis

et al. 2019

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“…Clinical studies involving ACE inhibitor therapy have shown increased plasma and tissue Ac‐SDKP concentrations, and some of the beneficial effects of ACE inhibitors in fibrotic diseases are attributable, in part, to increased Ac‐SDKP content (Kumar & Yin, ). It has been reported that Tβ4 is hydrolysed by meprin α and prolyl oligopeptidase, and meprin α knockout mice exhibited a significantly lower basal amount of Ac‐SDKP than wild‐type mice (Kumar et al., ).…”

Section: Discussionmentioning

confidence: 99%

Interaction of N‐acetyl‐seryl‐aspartyl‐lysyl‐proline with the angiotensin‐converting enzyme 2–angiotensin‐(1–7)–Mas axis attenuates pulmonary fibrosis in silicotic rats

Gao

Zhang

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?What are the effects of the antifibrotic peptide acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) on the angiotensin‐converting enzyme 2 (ACE2)–angiotensin‐(1–7)–Mas axis during the occurrence and progression of silicosis? What is the main finding and its importance?Ac‐SDKP inhibited lung fibrosis in rats exposed to silica by activation of the ACE2–angiotensin‐(1–7)–Mas axis. Angiotensin‐(1–7) potentially promotes Ac‐SDKP by increasing the level of meprin α, the major synthetase of Ac‐SDKP. Thus, the interaction Ac‐SDKP and angiotesin‐(1–7) in silicosis could provide a new therapeutic strategy. Abstract The central role of angiotensin‐converting enzyme (ACE) in the occurrence and progression of silicosis has been established. The antifibrotic peptide acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) can be degraded by ACE. The ACE2–angiotensin‐(1–7)–Mas axis is protective and acts to counterbalance the detrimental effects of ACE–angiotensin II (Ang II)–Ang II type 1 receptor and exerts antifibrotic effects. Here, we demonstrate an interaction between Ac‐SDKP and Ang‐(1–7) in the inhibition of collagen deposition and myofibroblast differentiation in rats exposed to silica. Treatment with Ac‐SDKP increased the level of ACE2–Ang‐(1–7)–Mas in rats or in cultured fibroblasts and decreased the levels of collagen type I and α‐smooth muscle actin. Furthermore, exogenous Ang‐(1–7) had similar antifibrotic effects and increased the level of meprin α, a major Ac‐SDKP synthetase, both in vivo and in vitro. Compared with non‐silicotic patients exposed to silica, the level of serum ACE was increased in patients with silicosis phase III; the levels of Ang II and Ang‐(1–7) were high in patients with silicosis phase II; and the level of Ac‐SDKP was high in the silicosis phase III group. These data imply that Ac‐SDKP and Ang‐(1–7) have an interactive effect as regulatory peptides of the renin–angiotensin system and exert antifibrotic effects.

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“…Originally reported as a hematopoiesis regulator that inhibits the proliferation of hematopoietic pluripotent stem cells (Frindel and Monpezat, 1989), AcSDKP is now implicated in many physiological processes, such as inflammation, fibrosis, angiogenesis, and apoptosis. Recently, AcSDKP has drawn considerable attention due to its anti-inflammatory properties (Kumar and Yin, 2018). Numerous studies have shown that AcSDKP exerts strong protective effects on several diseases involving the brain, heart, liver, and kidney; in part by reducing local inflammatory reactions (Chen et al, 2010;Worou et al, 2015;Zhang et al, 2017;Sharma et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Mitigates Experimental Colitis Through Inhibition of Intestinal Mucosal Inflammatory Responses via MEK-ERK Signaling

et al. 2020

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N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous immunomodulatory peptide that is generated from thymosin b4 (Tb4) through stepwise hydrolysis, involving meprin-a and prolyl endopeptidase (PREP). It is well acknowledged that AcSDKP exerts beneficial effects on multiple cardiovascular and renal diseases. However, the functional role of AcSDKP in inflammatory bowel disease (IBD) remains poorly understood. Here, we aimed to assess the content of AcSDKP in patients with IBD and investigate the impact of AcSDKP on intestinal inflammation in IBD. We found that in the inflamed mucosal specimens of patients with ulcerative colitis, the expression levels of Tb4 and meprin-a were decreased, while PREP was expressed at similar levels to non-inflamed mucosa. In vitro, AcSDKP inhibited the expression of proinflammatory factors in intestinal epithelial cells partially by reducing the activation of MEK-ERK signaling. In vivo studies showed that transgenic mice, with lower levels of AcSDKP, were more vulnerable to dextran sulfate sodium (DSS)-induced colitis and exhibited more severe intestinal inflammatory responses. On the other hand, exogenous AcSDKP infusion significantly attenuated the clinical symptoms and intestinal mucosal inflammation in DSS-induced mice. In conclusion, results from this study demonstrated the anti-inflammatory function of AcSDKP within the intestine and suggest that AcSDKP has a promising therapeutic potential for IBD treatment.

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The anti-inflammatory peptide Ac-SDKP: Synthesis, role in ACE inhibition, and its therapeutic potential in hypertension and cardiovascular diseases

Cited by 48 publications

References 132 publications

d‐amino acid modification protects N‐Acetyl‐seryl‐aspartyl‐lysyl‐proline from physiological hydroxylation and increases its antifibrotic effects on hepatic fibrosis

d‐amino acid modification protects N‐Acetyl‐seryl‐aspartyl‐lysyl‐proline from physiological hydroxylation and increases its antifibrotic effects on hepatic fibrosis

Interaction of N‐acetyl‐seryl‐aspartyl‐lysyl‐proline with the angiotensin‐converting enzyme 2–angiotensin‐(1–7)–Mas axis attenuates pulmonary fibrosis in silicotic rats

N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Mitigates Experimental Colitis Through Inhibition of Intestinal Mucosal Inflammatory Responses via MEK-ERK Signaling

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