Cigarette Smoking is Associated with PEDF Downregulation in the Myocardium
Authors: McHowat Jane , Adney Jacob , Jones Jacqueline , Patel Hetal , Hui Dawn 
Published: June 2021

Cigarette smoking is estimated to contribute to 10% of cardiovascular disease, resulting in approximately 6 million deaths per year worldwide. Despite the well‐established correlation between smoking and coronary artery disease, many fundamental questions regarding the effect of cigarette smoking on the myocardium itself remain unanswered. We have shown that smoking is associated with platelet‐activating factor (PAF) accumulation, an inflammatory metabolite that is implicated in ischemia/reperfusion injury and heart failure progression. PAF enhances matrix metalloproteinase (MMP) activation, which may contribute to downregulation of pigment epithelium‐derived factor (PEDF), a glycoprotein with anti‐inflammatory and antioxidative properties that can protect against endothelial damage, platelet aggregation and T–cell activation. Prior studies have indicated that PEDF inhibits calcium‐independent phospholipase A2 (iPLA2) to decrease downstream inflammatory pathways. We hypothesized that PAF accumulation and/or PEDF downregulation may directly contribute to smoking‐induced myocardial disease. We exposed mice to cigarette smoke (48 min/day, 5 days/week) for up to 6 months and measured biochemical and histological changes in the heart. Smoking resulted in increased iPLA2 activity (3.46 ± 0.21 to 5.76 ± 0.64 nmol/mg protein/min, p<0.01, n=4) and decreased PAF acetylhydrolase activity (PAF‐AH activity, 26.5 ± 0.06 to 14.8 ± 0.02 nmol/mg protein/min, p<0.01, n=4), changes that indicate increased PAF synthesis and decreased inactivation. Smoking was associated with increased MMP‐2 expression and downregulation of PEDF expression in the heart by immunoblot analysis. Following exposure to cigarette smoking, cardiac vessels in the mouse exhibited vascular wall thickening, particularly in the smooth muscle layer. Changes in the vessel wall were similar to those observed in PEDF knockout mice exposed to room air. Studies were then performed in atrial tissue removed from human heart during cardiac surgery (coronary artery bypass grafting, n=22; aortic valve surgery, n=2). Patients were separated into never smokers (n=10) and current smokers (n=14). There was no significant difference between the two groups for age, sex, number of diseased vessels, number of vessels bypassed, left ventricular ejection fraction or days of inotropy post‐op. Smokers had an increased history of prior myocardial infarction (p=0.003). An increase in iPLA2 activity was observed in atrial tissue from smokers when compared to never smokers (4.60 ± 0.21 nmol/mg protein/min for smokers, 2.70 ± 0.26 for never smokers, p<0.01). Additionally, PAF‐AH activity was decreased in smokers (34.0 ± 2.6 to 20.1 ± 1.5 nmol/mg protein/min, p<0.01), a change comparable to that observed in mice exposed to cigarette smoke. Immunoblot analysis of PEDF content in the human myocardium was reduced in smokers when compared to never smokers. These are the first data to implicate PEDF downregulation in smoking‐related cardiovascular disease. PEDF has been shown to improve ischemic cardiac function, inhibit cardiac fibrosis and is cardioprotective. Whether decreased PEDF expression in the myocardium of smokers contributes to compromised cardiac function following myocardial ischemic events, including the demands of cardiac surgery, remains to be determined.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.