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Downregulation of myocardial pigment epithelium‐derived factor in mice exposed to cigarette smoke: A possible mechanism for smoking‐related cardiovascular disease
Author(s) -
McHowat Jane,
Kuenzel Hannah,
Kispert Shan,
Marentette John,
Kolar Grant
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1011.3
Subject(s) - downregulation and upregulation , pedf , medicine , endocrinology , oxidative stress , inflammation , chemistry , angiogenesis , biochemistry , gene
Cigarette smoking is estimated to cause 10% of cardiovascular disease with approximately 6 million deaths per year worldwide. Despite the well‐established correlation between smoking and cardiovascular disease, many fundamental questions regarding underlying mechanisms 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. We hypothesized that PAF accumulation and/or PEDF downregulation may directly contribute to smoking‐induced cardiovascular disease. We exposed mice to cigarette smoke for up to 6 months and measured biochemical and histological changes in the heart. Smoking resulted in increased calcium‐independent phospholipase A 2 activity (3.46 ± 0.21 to 5.76 ± 0.64 nmol/mg protein/min, p<0.01, n=4) and decreased PAF acetylhydrolase activity (2.65 + 0.06 to 1.48 + 0.02 nmol/mg protein/min), 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. Immunohistochemical analysis demonstrated that the majority of PEDF was associated with cardiac myocytes and was reduced in animals exposed to cigarette smoke. Following exposure to cigarette smoking, cardiac vessels exhibited thickening of the vessel walls, particularly in the smooth muscle layer. Changes in the vessel wall were similar to those observed in PEDF knockout mice. These are the first data to implicate PEDF downregulation in smoking‐related cardiovascular disease. Support or Funding Information Saint Louis University Doisy Research Fund