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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 mug/kg per day, s.c.), (3) Ang II + captopril (100 mg/kg per day in drinking water), (4) Ang II + Ac-SDKP (400 mug/kg per day, s.c.), and (5) Ang II + Ac-SDKP (800 mug/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 mug/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 mug/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. (C) 2004 Lippincott Williams Wilkins.

Background An involvement of the renin angiotensin system in atrial fibrillation (AF) has been hypothesized, and ACE DD genotype has been suggested to influence the predisposition to AF. The aim of this study was to investigate the role of the ACE I/D polymorphism in relation to the different clinical forms of AF, lone and secondary nonvalvular atrial fibrillation (NVAF). Methods 510 consecutive patients with documented NVAF (106 patients had lone, and 404 secondary NVAF), and 520 controls with a negative history of cardiovascular disease have been studied. Results A significant difference in allele frequency between lone and secondary NVAF ( p =0.002) has been found. The ACE D allele was associated with the predisposition to lone NVAF under a dominant, recessive and additive model, both at univariate and multivariate analysis, after adjustment for age and gender (multivariate analysis: dominant OR=2.87, p =0.02; recessive OR=2.01, p =0.003; additive OR=4.47, p ACE D allele was significantly associated with secondary NVAF at both univariate and multivariate analysis under a recessive and additive, but not dominant, model (multivariate analysis: recessive OR=1.89, p =0.001; additive OR=2.50, p Conclusions This study highlights the role of ACE gene in predisposing to both lone and secondary NVAF, further contributing to penetrate the genetic mechanisms responsible for this complex disease. The clinical relevance of our results may be related to the possible characterization of subjects predisposed to NVAF in the absence of traditional risk factors, and to the use of ACE-inhibitors therapy able to improve the arrhythmogenic substrate.

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 mug/kg per day, s.c.), (3) Ang II + captopril (100 mg/kg per day in drinking water), (4) Ang II + Ac-SDKP (400 mug/kg per day, s.c.), and (5) Ang II + Ac-SDKP (800 mug/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 mug/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 mug/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. (C) 2004 Lippincott Williams Wilkins.