goralatide

N-Acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate for the N-terminal site of ACE.

Signaling Pathways >> Metabolic Enzyme/Protease >> Angiotensin-converting Enzyme (ACE)

Research Areas >> Cardiovascular Disease

Research Areas >> Inflammation/Immunology

Peptides

N-Acetyl-Ser-Asp-Lys-Pro is an endogenous tetrapeptide secreted by bone marrow and is ubiquitously found in plasma and various tissues. N-Acetyl-Ser-Asp-Lys-Pro is degraded specifically by ACE, and its plasma level rises substantially during ACE inhibitor therapy. N-Acetyl-Ser-Asp-Lys-Pro inhibits the proliferation of isolated cardiac fibroblasts but significantly stimulates the proliferation of vascular smooth muscle cells. Flow cytometry of rat cardiac fibroblasts treated with N-Acetyl-Ser-Asp-Lys-Pro shows significant inhibition of the progression of cells from G0/G1 phase to S phase of the cell cycle. In cardiac fibroblasts transfected with a Smad-sensitive luciferase reporter construct, N-Acetyl-Ser-Asp-Lys-Pro decreases luciferase activity by 55%. Moreover, phosphorylation and nuclear translocation of Smad2 is decreased in cardiac fibroblasts treated with N-Acetyl-Ser-Asp-Lys-Pro[1]. N-acetyl-seryl-aspartyl-lysyl-proline is a negative regulator of hematopoietic stem cell proliferation. N-acetyl-seryl-aspartyl-lysyl-proline is involved in the control of hematopoietic stem cell proliferation by preventing their recruitment into S-phase. N-acetyl-seryl-aspartyl-lysyl-proline appears to exert this function by blocking the action of a stem cell-specific proliferation stimulator and acts selectively on quiescent progenitors[2]. N-Acetyl-Ser-Asp-Lys-Pro inhibits collagenase expression and activation is associated with increased expression of TIMP-1 and TIMP-2. N-Acetyl-Ser-Asp-Lys-Pro does not alter collagenase or gelatinase activity in cardiac fibroblasts under basal conditions, but blunts the IL-1β-induced increase in total collagenase activity. Similarly, N-Acetyl-Ser-Asp-Lys-Pro normalizes the IL-1β-mediated increase in MMP-2 and MMP-9 activities and MMP-13 expression[3].

N-Acetyl-Ser-Asp-Lys-Pro prevents hypertension-induced inflammatory cell infiltration, collagen deposition, nephrin downregulation and albuminuria, which could lead to renoprotection in hypertensive mice[4].

The kinetics of N-Acetyl-Ser-Asp-Lys-Pro hydrolysis are determined by incubating enzymes (0.4 nM wild-type ACE, 0.3 nM ACE K959 963, and 9 nM ACE K361 365) with N-Acetyl-Ser-Asp-Lys-Pro over a concentration range of 0.35-40 μM, added to [3H]N-Acetyl-Ser-Asp-Lys-Pro (5 μCi). The reaction is stopped by freezing on dry ice, and samples are then analyzed[2].

Mice: 16-week-old C57BL/6J mice are treated with either placebo, DCOA (10 mg/10 g body weight subcutaneous) and 1% sodium chloride with 0.2% potassium chloride in drinking water (DOCA-salt) or DOCA-salt with Ac-SDKP (800 μg/kg per day) for 12 weeks. Bloof pressure, urine albumin, glomerular matrix, renal collagen content, monocyte/macrophage infiltration and glomerular nephrin expression are measured[4].

[1]. Rousseau A, et al. The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specificsubstrate of the N-terminal active site of human angiotensin-converting enzyme. J Biol Chem. 1995 Feb 24;270(8):3656-61.

[2]. Pokharel S, et al. N-acetyl-Ser-Asp-Lys-Pro inhibits phosphorylation of Smad2 in cardiac fibroblasts. Hypertension. 2002 Aug;40(2):155-61.

[3]. Rhaleb NE, et al. N-acetyl-Ser-Asp-Lys-Pro inhibits interleukin-1β-mediated matrix metalloproteinase activation in cardiac fibroblasts. Pflugers Arch. 2013 Oct;465(10):1487-95.

[4]. Rhaleb NE, et al. Renal protective effects of N-acetyl-Ser-Asp-Lys-Pro in deoxycorticosterone acetate-salt hypertensive mice. J Hypertens. 2011 Feb;29(2):330-8.

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