<i>N</i>-acetyl-seryl-aspartyl-lysyl-proline stimulates angiogenesis in vitro and in vivo

Wang, Dahai; Carretero, Oscar A.; Yang, Xiaoyi; Rhaleb, Nour-Eddine; Liu, Yunhe; Liao, Tang-Dong; Yang, Xiao‐Ping

doi:10.1152/ajpheart.00592.2004

Cited by 72 publications

(61 citation statements)

References 40 publications

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“…Ac-SDKP also promotes angiogenesis (16). Our laboratory previously found that Ac-SDKP stimulated endothelial cell proliferation, migration, and tube formation in vitro and increased myocardial capillary density in vivo (41). This angiogenic property of Ac-SDKP may favorably provide blood flow and oxygen supply to the damaged myocardium, thus improving cardiac function.…”

Section: Discussionmentioning

confidence: 95%

N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin

Liu¹,

D’Ambrosio²,

Liao³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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252

184

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Section: Discussionmentioning

confidence: 95%

N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin

Liu¹,

D’Ambrosio²,

Liao³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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252

184

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“…57 N-Acetyl-Seryl-Aspartyl-Lysyl-Proline N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP or goralatide) is a potent natural inhibitor of hematopoietic stem cell proliferation that is degraded mainly by ACE. 58,59 In vitro, Ac-SDKP is a potent angiogenic factor 60 and inhibits collagen production by cardiac fibroblasts, 61 whereas in vivo, it blocks collagen deposition in the left ventricle of rats with hypertension or myocardial infarction. 62 ACE inhibitor treatment results in a significant increase in plasma Ac-SDKP levels in humans, 63 and in rats, the exogenous application of Ac-SDKP exerts many effects (including inhibition of Ang II-induced cell proliferation, left ventricular macrophage/ mast cell infiltration, and collagen deposition) that are generally associated with ACE inhibitor therapy.…”

Section: Angiotensin 1-7mentioning

confidence: 99%

Signaling by the Angiotensin-Converting Enzyme

Fleming

2006

Circulation Research

161

119

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Abstract-Inhibition of the angiotensin-converting enzyme (ACE) protects against the progression of several cardiovascular diseases. Because of its dual role in regulating angiotensin II and bradykinin levels, the positive clinical effects of ACE inhibitors were thought to be the consequence of concomitant reductions in the production of angiotensin II and the degradation of bradykinin. Recent evidence suggests that some of the beneficial effects of ACE inhibitors on cardiovascular function and homeostasis can be attributed to novel mechanisms. These include the accumulation of the ACE substrate N-acetyl-seryl-aspartyl-lysyl-proline, which blocks collagen deposition in the injured heart, as well as the activation of an ACE signaling cascade that involves the activation of the kinase CK2 and the c-Jun N-terminal kinase in endothelial cells and leads to changes in gene expression. Moreover, at least one other ACE homologue (ACE2) is proposed to counteract the detrimental effects associated with the activation of the classical renin-angiotensin system. These data reveal hitherto unexpected levels of internal regulation of the renin-angiotensin system. (Circ Res. 2006;98:887-896.)

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“…Ac-SDKP, the product of T␤4 hydrolysis by meprin-␣ and POP, shares very similar properties with meprin-␣. It has been reported that Ac-SDKP promotes angiogenesis in cornea (43) and abdominal wall of the rat (26). The anti-inflammatory properties of Ac-SDKP have been shown in pathologies such as renal diseases, hypertension, and cardiovascular diseases (31,45).…”

Section: Discussionmentioning

confidence: 99%

The anti-inflammatory peptide Ac-SDKP is released from thymosin-β4 by renal meprin-α and prolyl oligopeptidase

Kumar

Nakagawa

Janic

et al. 2016

American Journal of Physiology-Renal Physiology

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The anti-inflammatory peptide Ac-SDKP is released from thymosin-␤4 by renal meprin-␣ and prolyl oligopeptidase. Am J Physiol Renal Physiol 310: F1026 -F1034, 2016. First published March 9, 2016 doi:10.1152/ajprenal.00562.2015.-N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide with antiinflammatory and antifibrotic properties. Previously, we have shown that prolyl oligopeptidase (POP) is involved in the Ac-SDKP release from thymosin-␤4 (T␤4). However, POP can only hydrolyze peptides shorter than 30 amino acids, and T␤4 is 43 amino acids long. This indicates that before POP hydrolysis takes place, T␤4 is hydrolyzed by another peptidase that releases NH2-terminal intermediate peptide(s) with fewer than 30 amino acids. Our peptidase database search pointed out meprin-␣ metalloprotease as a potential candidate. Therefore, we hypothesized that, prior to POP hydrolysis, T␤4 is hydrolyzed by meprin-␣. In vitro, we found that the incubation of T␤4 with both meprin-␣ and POP released Ac-SDKP, whereas no Ac-SDKP was released when T␤4 was incubated with either meprin-␣ or POP alone. Incubation of T␤4 with rat kidney homogenates significantly released Ac-SDKP, which was blocked by the meprin-␣ inhibitor actinonin. In addition, kidneys from meprin-␣ knockout (KO) mice showed significantly lower basal Ac-SDKP amount, compared with wild-type mice. Kidney homogenates from meprin-␣ KO mice failed to release Ac-SDKP from T␤4. In vivo, we observed that rats treated with the ACE inhibitor captopril increased plasma concentrations of Ac-SDKP, which was inhibited by the coadministration of actinonin (vehicle, 3.1 Ϯ 0.2 nmol/l; captopril, 15.1 Ϯ 0.7 nmol/l; captopril ϩ actinonin, 6.1 Ϯ 0.3 nmol/l; P Ͻ 0.005). Similar results were obtained with urinary Ac-SDKP after actinonin treatment. We conclude that release of Ac-SDKP from T␤4 is mediated by successive hydrolysis involving meprin-␣ and POP.N-acetyl-seryl-aspartyl-lysyl-proline; thymosin-␤4; meprin-␣; prolyl oligopeptidase; angiotensin-converting enzyme THE ANTI-INFLAMMATORY PEPTIDE N-acetyl-seryl-aspartyl-lysylproline (Ac-SDKP) was identified originally in the bone marrow (24). It has also been widely distributed in mammalian organs, plasma, urine, and circulating mononuclear cells (23,39,46). In animal diseases with hypertension, as well as cardiovascular and kidney disease, Ac-SDKP reduces inflammatory cell infiltration and collagen deposition in the heart, kidney, lung, and liver (14,15,33,34,37,44). Ac-SDKP is hydrolyzed by angiotensin-converting enzyme (ACE) and has a short half-life of 4.5 min in the circulation (16). Treatment with ACE inhibitors significantly increased plasma concentration of Ac-SDKP (2), and some of the ACE inhibitors protective effects were reported to be mediated by the increases in Ac-SDKP concentrations (34, 35).Thymosin-␤4 (T␤4) is a major G-actin-sequestering peptide that consists of 43 amino acids. Since it contains the Ac-SDKP sequence in its NH 2 -terminal, T␤4 is considered to be the precursor of 39). Our group has shown p...

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N-acetyl-seryl-aspartyl-lysyl-proline stimulates angiogenesis in vitro and in vivo

Cited by 72 publications

References 40 publications

N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin

N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin

Signaling by the Angiotensin-Converting Enzyme

The anti-inflammatory peptide Ac-SDKP is released from thymosin-β4 by renal meprin-α and prolyl oligopeptidase

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