ACE inhibition promotes upregulation of endothelial progenitor cells and neoangiogenesis in cardiac pressure overload
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany. Cardiovascular Research
(Impact Factor: 5.94).
05/2009; 83(1):106-14. DOI: 10.1093/cvr/cvp123
Inhibition of the angiotensin-converting enzyme (ACE) prevents maladaptive cardiac remodelling. Endothelial progenitor cells (EPC) from the bone marrow contribute to endothelial repair and neovascularization, effects that are potentially important during cardiac remodelling. We hypothesized that ACE inhibitors may exert beneficial effects during pressure-induced myocardial hypertrophy by regulating progenitor cell function.
In C57/Bl6 mice, development of cardiac hypertrophy induced by transaortic constriction (TAC) for 5 weeks was reduced by ramipril, 5 mg/kg p.o., independent of blood pressure lowering. Ramipril prevented TAC-induced apoptosis of cardiac myocytes and endothelial cells. On day 1 after TAC, upregulation of Sca-1(pos)/KDR(pos) EPC was observed, which was further increased by ramipril. EPC were persistently elevated in the TAC mice receiving vehicle treatment but not in the ramipril group after 5 weeks. These effects were independent of hypoxia-inducible factor-1alpha mRNA and protein expression. The ACE inhibitor but not TAC improved the migratory capacity of DiLDL(pos) EPC. Increased cardiac afterload induced upregulation of extracardiac neoangiogenesis. This effect was enhanced by ACE inhibition. Ramipril but not TAC markedly increased cardiac capillary density determined by the ratio of CD31(pos) cells to cardiomyocytes. Bone marrow transplantation studies revealed that TAC increased the percentage of bone marrow-derived GFP(pos) endothelial cells in the myocardium, and ramipril made this effect more pronounced.
ACE inhibition prevents pressure-induced maladaptive cardiac hypertrophy and increases intra- and extracardiac neoangiogenesis associated with the upregulation of EPC and amelioration of EPC migration. The regulation of progenitor cells from the bone marrow identifies a novel effect of ACE inhibitors during cardiac remodelling.
Available from: Marc S Penn
- "We have recently described an early EPC and SSEA1+ cell response to TAC prior to any evidence of cardiac dysfunction but not a c-kit+ CSC activation . Others have described elevated peripheral EPC levels, increased CSC in the myocardium, and decreased cardiac function in the late stages of cardiac pressure overload [9,42,43]. We now consider that endogenous stem cell activity could correspond to specific pathophysiological myocardial changes that occur in the setting of cardiac pressure overload; initially an increased metabolic requirement correlates with an angiogenic response (EPC and SSEA1+ cells), and later, as heart failure and dysfunction becomes evident and cardiac myocyte apoptosis begins, the CSC population gets activated . "
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ABSTRACT: Stage specific embryonic antigen 1+ (SSEA1+) cells have been described as the most primitive mesenchymal progenitor cell in the bone marrow. Cardiac injury mobilizes SSEA1+ cells into the peripheral blood but their in vivo function has not been characterized.
We generated animals with chimeric bone marrow to determine the fate and function of bone marrow SSEA1+ cells in response to acute cardiac pressure overload.
Lethally irradiated mice were transplanted with normal bone marrow where the wild-type SSEA1+ cells were replaced with green fluorescent protein (GFP) SSEA1+ cells. Cardiac injury was induced by trans-aortic constriction (TAC). We identified significant GFP+ cell engraftment into the myocardium after TAC. Bone marrow GFP+ SSEA1 derived cells acquired markers of endothelial lineage, but did not express markers of c-kit+ cardiac progenitor cells. The function of bone marrow SSEA1+ cells after TAC was determined by transplanting lethally irradiated mice with bone marrow depleted of SSEA1+ cells (SSEA1-BM). The cardiac function of SSEA1-BM mice declined at a greater rate after TAC compared to their complete bone marrow transplant counterparts and was associated with decreased bone marrow cell engraftment and greater vessel rarefication in the myocardium.
These results provide evidence for the recruitment of endogenous bone marrow SSEA1+ cells to the myocardium after TAC. We demonstrate that, in vivo, bone marrow SSEA1+ cells have the differentiation potential to acquire endothelial lineage markers. We also show that bone marrow SSEA1+ deficiency is associated with a reduced compensatory capacity to cardiac pressure overload, suggesting their importance in cardiac homeostasis. These data demonstrate that bone marrow SSEA1+ cells are critical for sustaining vascular density and cardiac repair to pressure overload.
Available from: Yagna PR Jarajapu
- "In yet another study, ACE inhibition by ramipril enhanced cardiac capillary density in the trans-aortic constriction-induced cardiac hypertrophy model. This effect was associated with increased numbers of BM-derived progenitor cells found within the myocardium . Furthermore, mobilization of APCs from BM in response to ischemic injury was potentiated by enalapril treatment in mice . "
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ABSTRACT: Discovery of angiotensin converting enzyme (ACE)-2 provided a strong impetus for the development of novel
therapeutic tools for the treatment of cardiovascular diseases (CVDs). Angiotensin (Ang)-(1-7), the product of ACE2, via activation of Mas receptor elicits cardiovascular protective effects to a large extent by counter-regulating ACE/Ang-II/AT1-receptor axis of renin angiotensin system (RAS).
Bone marrow (BM)-derived progenitor cells play an important role in cardiovascular homeostasis. Angiogenic precursor cells (APCs) have received tremendous attention in the recent years for their therapeutic application for treatment of CVDs, where cardiovascular tissue regeneration is the desired outcome. Autologous cell therapy is a better treatment option for patients with cardiovascular complications. However, circulating APCs from these patients are dysfunctional limiting their therapeutic utility. Thus ex vivo modification to restore their regenerative potential is essential to improve outcomes of autologous cell therapies in CVD.
Members of both pathological and protective axes of RAS have been identified in one or more types of BM-derived cells. Modulation of the function of APCs by Ang-II or Ang-(1-7) has now been implicated in the pathology and protection of cardiovascular systems, respectively. Thus, novel functions of RAS in the cardiovascular regenerative physiology and pharmacology are being unraveled. Accumulating evidence points to the ACE2/Ang-(1-7)/Mas axis as a promising target for the treatment of CVDs. The major focus of this review is to highlight the protective role of ACE2/Ang-(1-7)/Mas pathway in the reparative function of BM-derived cells for cardiovascular repair and regeneration.
Available from: Yvonne Alexander
- "Studies have demonstrated an increase in EPC number following administration of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors independently of cholesterol reduction and this might be another mechanism by which statin medications exert a cardioprotective effect . Angiotensin-converting enzyme inhibiting agents and angiotensin 2 receptor blockers have also been shown to have a positive effect on EPC number and function in the clinical setting . Other pharmacological strategies that have been shown to enhance EPC number include chemokines and cytokines such as erythropoietin and VEGF [46,47]. "
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ABSTRACT: Patients with systemic lupus erythematosus (SLE) have a greatly increased risk of cardiovascular disease. There is growing interest in the link between vascular damage and lupus-specific inflammatory factors. Impaired endothelial repair could account for the endothelial dysfunction in this patient group. This review describes the contribution that endothelial progenitor cells could play in the pathogenesis of premature vascular damage in this disease. The methods of isolation, detection, and characterization of endothelial progenitor cells, together with their potential role in repair of the endothelium and as a therapeutic target in SLE, are discussed.
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