p53 Mediates Cigarette Smoke–Induced Apoptosis of Pulmonary Endothelial Cells

Abstract

Exposure to cigarette smoke (CS) is the most common cause of emphysema, a debilitating pulmonary disease histopathologically characterized by the irreversible destruction of lung architecture. Mounting evidence links enhanced endothelial apoptosis causally to the development of emphysema. However, the molecular determinants of human endothelial cell apoptosis and survival in response to CS are not fully defined. Such determinants could represent clinically relevant targets for intervention. We show here that CS extract (CSE) triggers the death of human pulmonary macrovascular endothelial cells (HPAECs) through a caspase 9-dependent apoptotic pathway. Exposure to CSE results in the increased expression of p53 in HPAECs. Using the p53 inhibitor, pifithrin-a (PFT-a), and RNA interference (RNAi) directed at p53, we demonstrate that p53 function and expression are required for CSE-mediated apoptosis. The expression of macrophage migration inhibitory factor (MIF), an antiapoptotic cytokine produced by HPAECs, also increases in response to CSE exposure. The addition of recombinant human MIF prevents cell death from exposure to CSE. Further, the suppression of MIF or its receptor/binding partner, Jun activation domain-binding protein 1 (Jab-1), with RNAi enhances the sensitivity of human pulmonary endothelial cells to CSE via a p53-dependent (PFT-a-inhibitable) pathway. Finally, we demonstrate that MIF is a negative regulator of p53 expression in response to CSE, placing MIF upstream of p53 as an antagonist of CSE-induced apoptosis. We conclude that MIF can protect human vascular endothelium from the toxic effects of CSE via the antagonism of p53-mediated apoptosis.

Cigarette smoke-induced lung endothelial apoptosis and emphysema are associated with impairment of FAK and eIF2α

“…CSE has been shown to cause pulmonary EC apoptosis (Damico et al, 2011; Tuder et al, 2000). Consistently, we noted that both PAEC and LMVEC exposed to CSE for 6-24h displayed a significant increase in apoptosis, as indicated by caspase-3 cleavage (Fig.…”

“…Lung EC apoptosis is significantly increased in emphysematous lungs of human smokers (Kasahara et al, 2001). Cultured pulmonary EC undergo apoptosis after exposure to cigarette smoke extract (CSE) (Damico et al, 2011; Tuder et al, 2000). Additionally, lung EC-specific induction of apoptosis causes emphysematous-like change in mice (Giordano et al, 2008).…”

Cigarette Smoke Induces Akt Protein Degradation by the Ubiquitin-Proteasome System

“…Therefore, cigarette smoke is supposed to contribute to cell death, partly via Akt degradation and reduced phosphorylation of HDM2, resulting in an increase of p53 and p21. In human pulmonary artery endothelial cells, CSE induced p53, and inhibition of p53 by a pharmacological inhibitor or p53 siRNA resulted in significant blockade of cigarette smoke-induced apoptosis (45). In addition to p53 induction by decreased p-HDM2, cigarette smoke may exert its cytotoxic action by activation of p53 through the ASK1/p38 MAPK pathway.…”

Genetic Ablation of the Aryl Hydrocarbon Receptor Causes Cigarette Smoke-induced Mitochondrial Dysfunction and Apoptosis

“…As proposed by Calabrese and col-leagues (11), this apoptosis-proliferation imbalance suggests that excess apoptosis, coupled with reduced proliferation, causes loss of alveolar cells and eventual formation of emphysematous lesions. Many cells within the alveolar wall are sensitive to the toxic and apoptotic-inducing effects of cigarette smoke, including immune cells (12), endothelial (13,14) and epithelial cells (15), and fibroblasts (16,17). Both fibroblasts and epithelial cells rapidly undergo apoptosis after cigarette smoke exposure (16 -18) and increase antioxidant defense proteins (19 -22).…”