{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:06:48Z","timestamp":1791295608204,"version":"4.1.0"},"reference-count":43,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2008,3]]},"abstract":"<jats:p>High blood pressure (HBP) is an important risk factor for cardiac, renal, and vascular dysfunction. Excess inflammation is the major pathogenic mechanism for HBP-induced 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-\u03b1 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-\u03b1 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 \u00b1 1.06 mean fluorescent intensity for vehicle and 10.63 \u00b1 0.35 for Ac-SDKP; P &lt; 0.05]. Ac-SDKP also decreased galectin-3 and macrophage colony-stimulating factor-dependent macrophage migration. In addition, Ac-SDKP decreased secretion of TNF-\u03b1 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.<\/jats:p>","DOI":"10.1152\/ajpheart.00305.2007","type":"journal-article","created":{"date-parts":[[2008,1,5]],"date-time":"2008-01-05T01:54:33Z","timestamp":1199498073000},"page":"H1226-H1232","source":"Crossref","is-referenced-by-count":110,"title":["Novel anti-inflammatory mechanisms of<i>N<\/i>-Acetyl-Ser-Asp-Lys-Pro in hypertension-induced target organ damage"],"prefix":"10.1152","volume":"294","author":[{"given":"Umesh","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour-Eddine","family":"Rhaleb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saraswati","family":"Pokharel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Harding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saman","family":"Rasoul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar A.","family":"Carretero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","unstructured":"Adams DO, Koren HS.BCG-activated macrophages: comparison as effectors in direct tumor-cell cytotoxicity and antibody dependent cell-mediated cytotoxicity.Adv Exp Med Biol121B: 195\u2013201, 1979."},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.30.5.1015"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.75.1.23"},{"key":"R4","unstructured":"Bonnet D, Lemoine FM, Najman A, Guigon M.Comparison of the inhibitory effect of AcSDKP, TNF-\u03b1, TGF-\u03b2, and MIP-1\u03b1 on marrow-purified CD34+ progenitors.Exp Hematol23: 551\u2013556, 1995."},{"key":"R5","doi-asserted-by":"crossref","unstructured":"Bonnet D, Lemoine FM, Pontvert-Delucq S, Baillou C, Najman A, Guigon M.Direct and reversible inhibitory effect of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (Seraspenide) on the growth of human CD34+ subpopulations in response to growth factors.Blood82: 3307\u20133314, 1993.","DOI":"10.1182\/blood.V82.11.3307.bloodjournal82113307"},{"key":"R6","unstructured":"Cashman JD, Eaves AC, Eaves CJ.The tetrapeptide AcSDKP specifically blocks the cycling of primitive normal but not leukemic progenitors in long-term culture: evidence for an indirect mechanism.Blood84: 1534\u20131542, 1994."},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.106.084103"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1002\/stem.170339"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000125013.22494.c5"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.11.11.3835"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1002\/stem.170100"},{"key":"R12","unstructured":"Guigon M, Bonnet D, Lemoine FM, Kobari L, Permentier C, Mary JY, Najman A.Inhibition of human bone marrow progenitors by the synthetic tetrapeptide AcSDKP.Exp Hematol18: 1112\u20131115, 1990."},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(00)00460-4"},{"key":"R14","doi-asserted-by":"crossref","unstructured":"Kanasaki K, Haneda M, Sugimoto T, Shibuya K, Isono M, Isshiki K, Araki S, Uzu T, Kashiwagi A, Koya D.N-acetyl-seryl-aspartyl-lysyl-proline inhibits DNA synthesis in human mesangial cells via up-regulation of cell cycle modulators.Biochem Biophys Res Commun342: 758\u2013765, 2006.","DOI":"10.1016\/j.bbrc.2006.02.019"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000057544.95569.EC"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-05-1450"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2007.05.017"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.6.3254"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.3.779"},{"key":"R20","doi-asserted-by":"crossref","unstructured":"Luft FC, Mervaala E, M\u00fcller DN, Gross V, Schmidt F, Park JK, Schmitz C, Lippoldt A, Breu V, Dechend R, Dragun D, Schneider W, Ganten D, Haller H.Hypertension-induced end-organ damage. 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