Dysfunction of Endothelial Progenitor Cells from Smokers and Chronic Obstructive Pulmonary Disease Patients Due to Increased DNA Damage and Senescence

Abstract

Cardiovascular disease (CVD) is a major cause of death in smokers, particularly in those with chronic obstructive pulmonary disease (COPD). Circulating endothelial progenitor cells (EPC) are required for endothelial homeostasis, and their dysfunction contributes to CVD. To investigate EPC dysfunction in smokers, we isolated and expanded blood outgrowth endothelial cells (BOEC) from peripheral blood samples from healthy nonsmokers, healthy smokers, and COPD patients. BOEC from smokers and COPD patients showed increased DNA double-strand breaks and senescence compared to nonsmokers. Senescence negatively correlated with the expression and activity of sirtuin-1 (SIRT1), a protein deacetylase that protects against DNA damage and cellular senescence. Inhibition of DNA damage response by silencing of ataxia telangiectasia mutated (ATM) kinase resulted in upregulation of SIRT1 expression and decreased senescence. Treatment of BOEC from COPD patients with the SIRT1 activator resveratrol or an ATM inhibitor (KU-55933) also rescued the senescent phenotype. Using an in vivo mouse model of angiogenesis, we demonstrated that senescent BOEC from COPD patients are dysfunctional, displaying impaired angiogenic ability and increased apoptosis compared to cells from healthy nonsmokers. Therefore, this study identifies epigenetic regulation of DNA damage and senescence as pathogenetic mechanisms linked to endothelial progenitors' dysfunction in smokers and COPD patients. These defects may contribute to vascular disease and cardiovascular events in smokers and could therefore constitute therapeutic targets for intervention.

Endothelial Colony‐Forming Cells in Young Adults Born Preterm: A Novel Link Between Neonatal Complications and Adult Risks for Cardiovascular Disease

“…However, the evaluation of the impact of individual perinatal factors such as being small for gestational age and pregnancy‐induced hypertension, which have been previously linked to both adult cardiovascular health and EPCs, was limited because of the small number of preterm individuals with these conditions and the numbers with ECFC growth. Our incidence of ECFC colony growth was ≈60%, which is consistent with values reported 61. In addition, classical phenotypic characteristics of ECFC including clonogenic potential and formation of cobblestone‐patterned colonies, as well as in vitro vascular cord formation capacity and expression of CD31 and CD34, were observed and confirm the progenitor and endothelial nature of ECFC isolated from peripheral blood.…”

The role of bone marrow-derived endothelial progenitor cells and angiogenic responses in chronic obstructive pulmonary disease

“…EC-CFUs from smokers and COPD patients had increased DNA double-strand breaks and senescence compared to non-smokers (47). They further showed using an in vivo mouse model that EC-CFUs from COPD patients had impaired angiogenic activity and increased apoptosis (47). This is consistent with previous reports of increased DNA damage and senescence in peripheral lungs of normal smokes and to a greater degree in COPD patients compared to non-smoking controls (48-50).…”

“…Accordingly, it is not known whether these colonies arise directly from circulating EPCs or the progeny of myeloid cells that indirectly contribute to angiogenesis via paracrine processes (6,44). (47). EC-CFUs from smokers and COPD patients had increased DNA double-strand breaks and senescence compared to non-smokers (47).…”

Neovascularization Potential of Blood Outgrowth Endothelial Cells From Patients With Stable Ischemic Heart Failure Is Preserved

“…Specific reports on BOEC functionality and proliferation potential in various other disease states are, however, not uniform. Functional impairment has been reported, related to age,28 type 2 diabetes,29 obesity,30 pulmonary arterial hypertension,31 and smoking/chronic obstructive pulmonary disease 32. On the other hand, previous reports in treated coronary artery disease26, 33, 34 and arterial hypertension35 documented similar BOEC functionality in comparison to healthy controls.…”