Novel anti-inflammatory mechanisms ofN-Acetyl-Ser-Asp-Lys-Pro in hypertension-induced target organ damage

Abstract

High blood pressure (HBP) is an important risk factor for cardiac, renal, and vascular dysfunction. Excess inflammation is the major pathogenic mechanism for HBPinduced target organ damage (TOD). N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a tetrapeptide specifically degraded by angiotensin converting enzyme (ACE), reduces inflammation, fibrosis, and TOD induced by HBP. Our hypothesis is that Ac-SDKP exerts its anti-inflammatory effects by inhibiting: 1) differentiation of bone marrow stem cells (BMSC) to macrophages, 2) activation and migration of macrophages, and 3) release of the proinflammatory cytokine TNF-␣ by activated macrophages. BMSC were freshly isolated and cultured in macrophage growth medium. Differentiation of murine BMSC to macrophages was analyzed by flow cytometry using F4/80 as a marker of macrophage maturation. Macrophage migration was measured in a modified Boyden chamber. TNF-␣ release by activated macrophages in culture was measured by ELISA. Myocardial macrophage activation in mice with ANG II-induced hypertension was studied by Western blotting of Mac-2 (galectin-3) protein. Interstitial collagen deposition was measured by picrosirius red staining. We found that Ac-SDKP (10 nM) reduced differentiation of cultured BMSC to mature macrophages by 24.5% [F4/80 positivity: 14.09 Ϯ 1.06 mean fluorescent intensity for vehicle and 10.63 Ϯ 0.35 for Ac-SDKP; P Ͻ 0.05]. Ac-SDKP also decreased galectin-3 and macrophage colonystimulating factor-dependent macrophage migration. In addition, Ac-SDKP decreased secretion of TNF-␣ by macrophages stimulated with bacterial LPS. In mice with ANG II-induced hypertension, Ac-SDKP reduced expression of galectin-3, a protein produced by infiltrating macrophages in the myocardium, and interstitial collagen deposition. In conclusion, this study demonstrates that part of the anti-inflammatory effect of Ac-SDKP is due to its direct effect on BMSC and macrophage, inhibiting their differentiation, activation, and cytokine release. These effects explain some of the anti-inflammatory and antifibrotic properties of Ac-SDKP in hypertension. macrophages; inflammation; activation; angiotensin II HYPERTENSION LEADS TO CARDIAC, renal, and vascular damage. The mechanisms of target organ damage have not been fully elucidated. There is evidence that inflammation contributes to end organ damage (20). We have shown that in ANG IIinduced hypertension (32), as well as in renovascular hypertension (25, 35), mineralocorticoid-salt hypertension (26, 28), spontaneously hypertensive rats (9), and heart failure postmyocardial infarction (24), N-acetyl-seryl-aspartyl-lysyl-proline

Galectin-3 is a marker of myocardial and vascular fibrosis in Kawasaki disease patients with giant aneurysms

“…Experiments in hypertensive rats have demonstrated that the naturally occurring tetra-peptide, N-acetyl-ser-asp-lys-pro (AcSDKP) reduces myocardial inflammation and prevents fibrosis mediated by Gal-3 [27,28]. In vitro experiments have also demonstrated inhibition of epithelial-to-mesenchymal transition in tissue culture [29].…”

Galectin-3 and the Development of Heart Failure after Acute Coronary Syndrome: Pilot Experience from PROVE IT-TIMI 22

“…In patients with chronic HF, galectin-3 concentrations have been correlated with markers of extracellular matrix turnover, such as type III amino-terminal propeptide of procol- lagen (PIIINP) and matrix metalloproteinase 2 (MMP-2), implying a relationship between macrophage activation and collagen turnover (18 ). Intriguingly, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a monocyte-derived antiinflammatory and antifibrotic peptide that is degraded by ACE, inhibits galectin-3 expression in the left ventricle and reduces galectin-3-induced macrophage activation and migration (19 ). In a rat model, intrapericardial infusion of Ac-SDKP mitigated many of the adverse effects of galectin-3, leading to reduced myocardial macrophage and mast cell density, decreased left ventricular collagen burden, and improved diastolic and systolic function (4 ).…”

Involvement of galectin-3 in cadmium-induced cardiac toxicity

“…It has shown that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) prevents inflammation, cell proliferation and fibrosis in the heart and kidney in a ANG II-induced hypertension model. They found that galectin-3 expression increased in left ventricular remodeling together with inflammatory markers IL-6, transforming growth factor-β (TGF-β), and TNF-α (22). Liu et al (23) recently showed that the co-infusion of Ac-SDKP with galectin-3 into the pericardial sac, inhibited fibrosis and inflammation and decreased cardiac dysfunction.…”