ACE inhibition promotes upregulation of endothelial progenitor cells and neoangiogenesis in cardiac pressure overload.
ABSTRACT 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.
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ABSTRACT: The potential association between arterial stiffening and circulating endothelial progenitor cells (EPCs) in patients with essential hypertension was investigated. Pulse wave velocity (PWV) was used to evaluate arterial stiffness in 24 patients with essential hypertension and 19 healthy controls. Blood samples were taken and immunostained with antibodies against the cell surface markers CD34, CD45, and CD133. Using flow cytometry, EPCs as a population of CD45−/CD34+/CD133+ cells were measured. Hypertensive patients were not found to have higher levels of circulating CD45−/CD34+/CD133+ compared with the control group (0.0026%±0.0031% vs 0.0023%±0.0023%, respectively; P=.7). Correlation analysis revealed a strong association between the number of CD45−/CD34+/CD133+ cells and PWV (r=0.58, P<.001), indicating that hypertensive patients with increased PWV have a greater percentage of CD45−/CD34+/CD133+ cells. Data showed a correlation between the number of circulating CD45−/CD34+/CD133+ cells and arterial stiffness, suggesting that those cells might have a role in arterial remodeling.Journal of Clinical Hypertension 03/2014; · 2.36 Impact Factor
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ABSTRACT: In addition to the well-characterized circulating renin-angiotensin system (RAS), local RAS has been identified recently in diverse tissues and organs. The presence of key components of the RAS in local tissues is important for our understanding of the patho-physiological mechanism(s) of several metabolic diseases, and may serve as a major therapeutic target for cardiometabolic syndromes. Locally generated and physiologically active RAS components have functions that are distinct from the classical vasoconstriction and fluid homeostasis actions of systemic RAS and cater specifically for local tissues. Local RAS can affect islet-cell function and structure in the adult pancreas as well as proliferation and differentiation of pancreatic stem/progenitor cells during development. Differentiation of stem/progenitor cells into insulin-expressing cells suitable for therapeutic transplantation offers a desperately needed new approach for replacement of glucose-responsive insulin producing cells in diabetic patients. Given that the generation of functional and transplantable islet cells has proven to be difficult, elucidation of RAS involvement in cellular regeneration and differentiation may propel pancreatic stem/progenitor cell development and thus β-cell regeneration forward. This review provides a critical appraisal of current research progress on the role of the RAS, including the newly characterized ACE2/Ang-(1-7)/Mas axis in the proliferation, differentiation, and maturation of pancreatic stem/progenitor cells. It is thus plausible to propose that the AT1 stimulation could be a repair mechanism involving the AT2R as well as the ACE2/Ang-(1-7)/Mas axis in directing β-cell development in diabetic patients using genetic and pharmaceutical manipulation of the RAS.Molecular and Cellular Endocrinology 08/2013; · 4.04 Impact Factor
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ABSTRACT: Hypertension, the condition characterized by sustained elevated blood pressure, affects over 25% of adults in developed countries and is accompanied by pathological cardiac remodeling (i.e., hypertrophy and fibrosis), thus being a major risk factor for cardiac failure. Life style, the environment, genetic factors, diabetes or obesity can all promote development and progression of hypertension associated cardiovascular disease in part because these conditions induce an excess production of pro-hypertensive, pro-hypertrophic and pro-fibrotic agonists. Here we review signaling pathways shared by major agonists including angiotensin II, catecholamines and endothelins. At the cellular level, these agonists initiate disease signaling by activating cognate G protein-coupled receptors (GPCRs). Early events in agonist-signaling include Ca(2+) release from intracellular stores, Ca(2+) uptake from extracellular millieu into cells and reactive oxygen species (ROS) generation by NADPH oxidase. ROS production in turn contributes to activation of matrix metalloproteinases (MMPs) and 'a disintegrin and metalloproteinases' (ADAMs). Activated MMPs and ADAMs cleave growth factors, cytokines as well as cell surface receptors, including GPCRs. Excessive activation of MMPs and ADAMs links agonist receptors with transcription and translation of disease-associated genes, including those of MMPs and ADAMs. Recent research indicates a complex and dynamic regulation of MMPs and ADAMs activity and expression by agonists, which poses a significant challenge to strategies aiming at targeting specific MMPs or ADAMs in cardiovascular disease.Current Hypertension Reviews 08/2012; 8(3):159-180.