Cardiovascular Program: sPLA2 in the Cardiovascular System
Of the ten different isoforms of 
identified to date, groups IIA, V and X appear to be involved in the development of atherosclerosis and ischemia/reperfusion injury.
and Atherosclerosis
Atherosclerosis was once considered to be caused by elevated blood levels of cholesterol. However, current evidence suggests that atherosclerosis is an inflammatory disease [2,3,4].
The non-clinical data describing the role of in the development of atherosclerosis was recently summarized in a review by Nancy Webb from the University of Kentucky [5]. Transgenic mice expressing human IIA (in a strain that lacks endogenous expression of the enzyme) resulted in spontaneous atherosclerotic lipid deposition [6]. These mice had no evidence of high cholesterol levels but reduced HDL and elevated VLDL/LDL levels were noted and the changes in lipoproteins correlated with atherosclerotic lesion size. Group V specifically, has been shown to be a key enzyme in the process of atherosclerosis and associated with a nearly 3-fold increase in the occurrence of disease [7,8].
There are several mechanisms by which may be involved in the development of atherosclerosis. Hydrolysis of LDL and HDL lipoproteins by produces small dense atherogenic LDL particles and can enhance HDL catabolism, decreasing the capacity of HDL to mediate cellular cholesterol efflux from macrophages. The modification of LDL also results in increased retention of lipoprotein particles in the vessel wall [9,10]. The modified LDL retained in the vessel wall is more prone to oxidation and uptake by macrophages thereby promoting foam cell formation [11,12]. Hydrolysis of phospholipids by also has pro-inflammatory effects including generation of bioactive lipids that promote vascular disease and increase the collagen content and macrophage infiltration of the atherosclerotic plaque [13].
In the clinical setting, is a significant risk factor for clinical coronary events among patients with stable coronary artery disease [14]. Increased activity of is also associated with endothelial dysfunction in patients with CAD [15].
and Ischemia-reperfusion injury
It is well established that inflammation in the reperfused myocardium plays a significant role in the overall extent of myocardial damage. Elevated levels of or increased amounts of enzyme activity are predictive of coronary events following interventional procedures such as stent placement and coronary angioplasty [16,17].
has been implicated in acute coronary syndromes (ACS) as well as non-ST and ST-elevation myocardial infarction (MI) [18,19]. Following ischemia IIA can bind to ischemically challenged cardiomyocytes and adversely affect their survival through a variety of mechanisms including direct cytotoxic effects, as well as through facilitation of the inflammatory response. During the acute phase of MI, or unstable angina, levels are elevated. The rise in enzyme levels becomes significant within 6–12 hours following the onset of the MI [20]. The rise in levels precedes that of CRP in both acute MI and unstable angina, and group V has been demonstrated in the myocardium during the acute phase of the infarct [21]. In patients with ACS or AMI, IIA levels and activity at the time of presentation are predictive for future coronary events [22,23,24]. Inhibition of in experimental models of acute MI reduced myocardial necrosis by over 50% [25].
in Healthy Males and Females
Observational and epidemiologic data indicate that both levels and activity are associated with future CAD in apparently healthy men and women and can identify patients at high risk for cardiovascular events [26,27].