OBJECTIVE: N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a potent natural inhibitor of hematopoietic stem cell proliferation which is degraded mainly by angiotensin-converting enzyme (ACE). In vitro, Ac-SDKP inhibits collagen production by cardiac fibroblasts; while in vivo it blocks collagen deposition in the left ventricle (LV) of rats with hypertension or myocardial infarction (MI). In addition, it reportedly prevents and reverses macrophage infiltration in the LV of rats with MI. We tested the hypothesis that when Ac-SDKP is infused at doses that cause plasma concentrations similar to those observed after ACE inhibition, it mimics the anti-inflammatory and antifibrotic effects of ACE inhibitors (ACEi) in the heart, and, further, that these effects are independent of changes in blood pressure. DESIGN AND METHODS: Rats were divided into five groups: (1) controls, (2) Ang II (750 microg/kg per day, s.c.), (3) Ang II + captopril (100 mg/kg per day in drinking water), (4) Ang II + Ac-SDKP (400 microg/kg per day, s.c.), and (5) Ang II + Ac-SDKP (800 microg/kg per day, s.c.). We measured LV cell proliferation, inflammatory cell infiltration, cytokine expression, hypertrophy and fibrosis. RESULTS: Plasma Ac-SDKP was five-fold higher in rats given ACEi and four- and ten-fold higher in rats given 400 and 800 microg/kg per day Ac-SDKP, respectively. ACEi significantly decreased Ang II-induced cell proliferation (Ki-67), LV macrophage/mast cell infiltration, transforming growth factor-beta, connective tissue growth factor and collagen deposition without affecting hypertension, LV hypertrophy or myocyte cross-sectional area, and these effects were mimicked by exogenous Ac-SDKP (400 microg/kg per day) which raised plasma Ac-SDKP to levels similar to ACEi. BP was not decreased by either ACEi or Ac-SDKP. CONCLUSIONS: We concluded that Ac-SDKP may be an important mediator of the anti-inflammatory and antifibrotic effects of ACEi in hypertension independent of its hemodynamic effects.
OBJECTIVE: N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a potent natural inhibitor of hematopoietic stem cell proliferation which is degraded mainly by angiotensin-converting enzyme (ACE). In vitro, Ac-SDKP inhibits collagen production by cardiac fibroblasts; while in vivo it blocks collagen deposition in the left ventricle (LV) of rats with hypertension or myocardial infarction (MI). In addition, it reportedly prevents and reverses macrophage infiltration in the LV of rats with MI. We tested the hypothesis that when Ac-SDKP is infused at doses that cause plasma concentrations similar to those observed after ACE inhibition, it mimics the anti-inflammatory and antifibrotic effects of ACE inhibitors (ACEi) in the heart, and, further, that these effects are independent of changes in blood pressure. DESIGN AND METHODS: Rats were divided into five groups: (1) controls, (2) Ang II (750 microg/kg per day, s.c.), (3) Ang II + captopril (100 mg/kg per day in drinking water), (4) Ang II + Ac-SDKP (400 microg/kg per day, s.c.), and (5) Ang II + Ac-SDKP (800 microg/kg per day, s.c.). We measured LV cell proliferation, inflammatory cell infiltration, cytokine expression, hypertrophy and fibrosis. RESULTS: Plasma Ac-SDKP was five-fold higher in rats given ACEi and four- and ten-fold higher in rats given 400 and 800 microg/kg per day Ac-SDKP, respectively. ACEi significantly decreased Ang II-induced cell proliferation (Ki-67), LV macrophage/mast cell infiltration, transforming growth factor-beta, connective tissue growth factor and collagen deposition without affecting hypertension, LV hypertrophy or myocyte cross-sectional area, and these effects were mimicked by exogenous Ac-SDKP (400 microg/kg per day) which raised plasma Ac-SDKP to levels similar to ACEi. BP was not decreased by either ACEi or Ac-SDKP. CONCLUSIONS: We concluded that Ac-SDKP may be an important mediator of the anti-inflammatory and antifibrotic effects of ACEi in hypertension independent of its hemodynamic effects.
Authors: S Kim; K Ohta; A Hamaguchi; T Omura; T Yukimura; K Miura; Y Inada; T Wada; Y Ishimura; F Chatani Journal: Hypertension Date: 1994-08 Impact factor: 10.190
Authors: M Azizi; A Rousseau; E Ezan; T T Guyene; S Michelet; J M Grognet; M Lenfant; P Corvol; J Ménard Journal: J Clin Invest Date: 1996-02-01 Impact factor: 14.808
Authors: Cesar A Romero; Nitin Kumar; Pablo Nakagawa; Morel E Worou; Tang-Dong Liao; Edward L Peterson; Oscar A Carretero Journal: Am J Physiol Renal Physiol Date: 2018-11-07
Authors: Allie Y Chen; Rebecca N Adamek; Benjamin L Dick; Cy V Credille; Christine N Morrison; Seth M Cohen Journal: Chem Rev Date: 2018-09-07 Impact factor: 60.622
Authors: Angela L Zachman; Spencer W Crowder; Ophir Ortiz; Katarzyna J Zienkiewicz; Christine M Bronikowski; Shann S Yu; Todd D Giorgio; Scott A Guelcher; Joachim Kohn; Hak-Joon Sung Journal: Tissue Eng Part A Date: 2012-10-19 Impact factor: 3.845
Authors: James A Iwaz; Elizabeth Lee; Hermineh Aramin; Danilo Romero; Navaid Iqbal; Matt Kawahara; Fatima Khusro; Brian Knight; Minal V Patel; Sumita Sharma; Alan S Maisel Journal: Drugs Date: 2016-02 Impact factor: 9.546
Authors: Xiaojun Liu; Christopher O C Bellamy; Matthew A Bailey; Linda J Mullins; Donald R Dunbar; Christopher J Kenyon; Gillian Brooker; Surasak Kantachuvesiri; Klio Maratou; Ali Ashek; Allan F Clark; Stewart Fleming; John J Mullins Journal: J Biol Chem Date: 2009-03-23 Impact factor: 5.157