Abstract 20563: Hyperhomocysteinemia Induces Vascular Remodeling During Atherosclerosis in Pon1 Knockout Mice
Background: Hyperhomocysteinemia (HHcy) is an independent risk factor for various cardiovascular diseases including hypertension, coronary artery disease and atherosclerosis. Previous studies have reported the anti-atherogenic properties of paraoxynase1 (PON1) through its homocysteine thiolactonase activity. Studies from our lab have shown abnormal matrix remodeling due to elevated MMP-9 expression, decreased vascular connexins (37 & 40) and endothelial dysfunction during HHcy. In the current study we examine the role of homocysteine and its effect on vascular remodeling during atherosclerosis in PON1 knockout mice. We hypothesize that PON1 knockout mice develop HHcy that induces MMP-9 expression and causes decreased Akt/ eNOS expression leading to vascular remodeling in atherosclerosis.
Methods: PON1 knockout mice were fed on atherogenic diet for 15 weeks as atherosclerosis disease model and compared with C57BL/6J (wild type) controls. Blood pressure was measured by tail cuff method and cardiovascular function and plaque formation was assessed in coronary, carotid, thoracic and abdominal aorta arteries by ultrasound. Plasma homocysteine levels were measured by High performance liquid chromatography. Protein expression of MMP-9, phosphorylated Akt, eNOS, connexin 37 and 40 were evaluated by western blot and immunohistochemistry.
Results: PON1 KO mice with atherogenic diet developed atherosclerosis and elevated blood pressures compared to their controls. Ultrasound revealed decreased left ventricular ejection fraction and plaque formation in abdominal aorta and carotid arteries. MMP-9 expression was up regulated and that of Akt and eNOS was down regulated. The expression of connexin 37 & 40 was decreased in PON1 mice showing atherosclerotic changes. Our results suggest that PON1 knockout mice develop HHcy that induces MMP-9 expression and causes decreased Akt/ eNOS expression leading to vascular dysfunction in atherosclerosis.
Author Disclosures: S. Givvimani: None. S. Pushpakumar: None. S. Kundu: None. V. Doyle: None. N. Narayanan: None. N. Metreveli: None. S.C. Tyagi: None.
- © 2014 by American Heart Association, Inc.