Cigarette Smoke Reduces Fatty Acid Catabolism, Leading to Apoptosis in Lung Endothelial Cells: Implication for Pathogenesis of COPD

Abstract

Endothelial cell (EC) apoptosis contributes to cigarette smoke (CS)-induced pulmonary emphysema. Metabolism of glucose, glutamine, and fatty acid is dysregulated in patients with chronic obstructive pulmonary disease (COPD). Whether CS causes metabolic dysregulation in ECs leading to development of COPD remains elusive. We hypothesized that CS alters metabolism, resulting in apoptosis in lung ECs. To test this hypothesis, we treated primary mouse pulmonary microvascular ECs (PMVECs) with CS extract (CSE) and employed PMVECs from healthy subjects and COPD patients. We found that mitochondrial respiration was reduced in CSE-treated PMVECs and in PMVECs from COPD patients. Specifically, oxidation of fatty acids (FAO) was reduced in these cells, which linked to reduced carnitine palmitoyltransferase 1a (Cpt1a), an essential enzyme for carnitine shuttle. CSE-induced apoptosis was further increased when cells were treated with a specific Cpt1 inhibitor etomoxir or transfected with Cpt1a siRNA. L-Carnitine treatment augmented FAO but attenuated CSE-induced apoptosis by upregulating Cpt1a. CSE treatment increased palmitate-derived ceramide synthesis, which was reduced by L-carnitine. Although CSE treatment increased glycolysis, inhibiting glycolysis with 2-deoxy-d-glucose had no effects on CSE-mediated apoptosis in lung ECs. Conclusively, FAO reduction increases ceramide and apoptosis in lung ECs treated with CSE, which may contribute to the pathogenesis of COPD/emphysema.

Effect of lentivirus-mediated CFTR overexpression on oxidative stress injury and inflammatory response in the lung tissue of COPD mouse model

“…However, the levels of macrophage, T cell, neutrophil, and eosinophil in the lungs of patients with pulmonary emphysema were increased multiple-folds compared with the normal group. This finding suggests that the inflammatory response toward smoke is elevated in patients with pulmonary emphysema [17]. In the studies using mouse models exposed to chronic cigarette smoke, amplified inflammatory cells including phagocyte, neutrophil, and T cell were observed in lung, and these cells and mediators were found to participate in the COPD chronic inflammation and affect the balance between oxidation and antioxidation [18,19].…”

Prohibitin Protects Against Cigarette Smoke Extract-Induced Cell Apoptosis in Cultured Human Pulmonary Microvascular Endothelial Cells

“…In the present study, we have investigated the protective ability of prohibitin overexpression in CSE exposure associated mitochondrial dysfunction, ROS generation, oxidative DNA damage and apoptosis in HPMECs. CSE may induce apoptosis in bronchial epithelial cells, endothelial cells and human airway smooth muscle cells (ASMCs) [11][12][13][14] CSE may cause injury in mitochondrial morphology and function and induce apoptosis via an intrinsic apoptotic pathway, which involves mitochondrial fragmentation and the disruption of mitochondrial membrane integrity, inhibit of mitochondrial respiration and release of cytochrome c, as well as changed expression levels of pro-apoptotic and anti-apoptotic molecules [13,[15][16][17][18]. A previous study has demonstrated that prohibitin decrease the apoptosis of endothelial cells in response to glyLDL [19].…”

Prohibitin protects against cigarette smoke extract-induced cell apoptosis in cultured human pulmonary microvascular endothelial cells

“…CSE may induce apoptosis in bronchial epithelial cells, endothelial cells and human airway smooth muscle cells (ASMCs) [11][12][13][14] CSE may cause injury in mitochondrial morphology and function and induce apoptosis via an intrinsic apoptotic pathway, which involves mitochondrial fragmentation and the disruption of mitochondrial membrane integrity, inhibit of mitochondrial respiration and release of cytochrome c, as well as changed expression levels of pro-apoptotic and anti-apoptotic molecules [13,[15][16][17][18]. A previous study has demonstrated that prohibitin decrease the apoptosis of endothelial cells in response to glyLDL [19].…”