N-Acetyl-Ser-Asp-Lys-Pro is an endogenous tetrapeptide secreted by bone marrow, which is a specific substrate for the N-terminal site of angiotensin-converting enzyme (ACE) [1]. N-Acetyl-Ser-Asp-Lys-Pro inhibits hematopoietic stem cells from entering the S phase, participates in the regulation of hematopoietic stem cell proliferation, and can block a stem cell-specific proliferation stimulating factor, selectively acting on quiescent progenitors [2]. N-Acetyl-Ser-Asp-Lys-Pro has been widely used to inhibit the differentiation of hematopoietic stem cells and tissue fibrosis[3].
In vitro, N-Acetyl-Ser-Asp-Lys-Pro treatment (1nM) for 24 hours significantly inhibited the inhibitory effect of S17092 (100μg/ml) on the proliferation of U87-MG cells, and induced Akt phosphorylation[4]. Treatment with 1nM N-Acetyl-Ser-Asp-Lys-Pro for 24 hours significantly inhibited the cell cycle progression of rat cardiac fibroblasts from the G0/G1 phase to the S phase, and led to a decrease in the phosphorylation and nuclear translocation of Smad2[5]. Treatment with 100nM N-Acetyl-Ser-Asp-Lys-Pro for 72 hours significantly inhibited the increase in MMP-2 and MMP-9 protein levels induced by IL-1β in rat cardiac fibroblasts, and reduced collagenase activity[6].
In vivo, N-Acetyl-Ser-Asp-Lys-Pro treatment via daily subcutaneous injection at a dose of 800μg/kg for 3 weeks alleviated proteinuria and renal fibrosis in the hypertensive rat model induced by 5/6 nephrectomy, and improved renal function[7]. Daily subcutaneous injection of 800μg/kg dose of N-Acetyl-Ser-Asp-Lys-Pro was administered for 12 weeks to prevent inflammatory cell infiltration, collagen deposition, downregulation of renin expression and proteinuria in hypertensive mice [8].
References:
[1] Stéphan J P, Melaine N, Ézan E, et al. Source, catabolism and role of the tetrapeptide N-acetyl-ser-asp-lys-Pro within the testis[J]. Journal of Cell Science, 2000, 113(1): 113-121.
[2] Rousseau A, Michaud A, Chauvet M T, et al. The hemoregulatory peptide N-Acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal active site of human angiotensin-converting enzyme (∗)[J]. Journal of Biological Chemistry, 1995, 270(8): 3656-3661.
[3] Douglas R G, Ehlers M R, Sturrock E D. Antifibrotic peptide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP): opportunities for angiotensin-converting enzyme inhibitor design[J]. Clinical & Experimental Pharmacology & Physiology, 2013, 40(8).
[4] Hu P, Li B, Zhang W, et al. AcSDKP regulates cell proliferation through the PI3KCA/Akt signaling pathway[J]. PloS one, 2013, 8(11): e79321.
[5] Pokharel S, Rasoul S, Roks A J M, et al. N-acetyl-Ser-Asp-Lys-Pro inhibits phosphorylation of Smad2 in cardiac fibroblasts[J]. Hypertension, 2002, 40(2): 155-161.
[6] Rhaleb N E, Pokharel S, Sharma U C, et al. N-acetyl-Ser-Asp-Lys-Pro inhibits interleukin-1β-mediated matrix metalloproteinase activation in cardiac fibroblasts[J]. Pflügers Archiv-European Journal of Physiology, 2013, 465(10): 1487-1495.
[7] Liao T D, Yang X P, D'Ambrosio M, et al. N-acetyl-seryl-aspartyl-lysyl-proline attenuates renal injury and dysfunction in hypertensive rats with reduced renal mass: council for high blood pressure research[J]. Hypertension, 2010, 55(2): 459-467.
[8] Rhaleb N E, Pokharel S, Sharma U, et al. Renal protective effects of N-acetyl-Ser-Asp-Lys-Pro in deoxycorticosterone acetate–salt hypertensive mice[J]. Journal of hypertension, 2011, 29(2): 330-338.
N-Acetyl-Ser-Asp-Lys-Pro是骨髓分泌的一种内源性四肽，是angiotensin-converting enzyme (ACE)的N末端位点的特异性底物[1]。N-Acetyl-Ser-Asp-Lys-Pro可抑制造血干细胞进入S期，参与调控造血干细胞增殖，并能阻断一种干细胞特异性增殖刺激因子，选择性地作用于静止期祖细胞[2]。N-Acetyl-Ser-Asp-Lys-Pro已被广泛用于抑制造血干细胞分化和组织纤维化[3]。
在体外，1nM的N-Acetyl-Ser-Asp-Lys-Pro处理U87-MG细胞24小时，显著抑制了S17092对细胞增殖的抑制作用，并诱导了Akt磷酸化[4]。1nM的N-Acetyl-Ser-Asp-Lys-Pro处理大鼠心脏成纤维细胞24小时，显著抑制了细胞周期从G0/G1期向S期的进程，并导致Smad2磷酸化和核转位减少[5]。100nM的N-Acetyl-Ser-Asp-Lys-Pro处理大鼠心脏成纤维细胞72小时，显著抑制了IL-1β诱导的MMP-2和MMP-9蛋白水平升高，并降低了胶原酶活性[6]。
在体内，每日皮下注射800μg/kg剂量的N-Acetyl-Ser-Asp-Lys-Pro，持续3周，减轻了5/6肾切除诱导的高血压大鼠模型中的蛋白尿和肾纤维化，并改善了肾功能[7]。每日皮下注射800μg/kg剂量的N-Acetyl-Ser-Asp-Lys-Pro，持续12周，可预防高血压小鼠的炎症细胞浸润、胶原沉积、肾素表达下调和蛋白尿[8]。