## 4 Discussion
Phospholipase A2 (PLA2) catalyzes the hydrolysis of membrane glycerophospholipids to liberate free fatty acids. It has been reported that oxidized LDL can activate PLA2 to supply fatty acids for Chol esterification in macrophages [32]. 7 KCh induces apoptosis in macrophages by a mechanism involving cPLA2, but it also forms part of a second message when esterified by SOAT [33]. Pharmacological inhibition [34] or knockout [35] of macrophage SOAT results in increased plaque size in animal models of atherosclerosis. An increase in apoptotic cells was observed in the _Soat1_-/ - lesions. The failure to metabolize oxidized Chol properly by macrophages may contribute to cytotoxicity and pathogenesis of vascular diseases. The present study demonstrated that 7 KCh induces metabolic reprogramming in cardiomyocytes. Such a process is probably implicated in the pathogenesis of cardiovascular diseases. The transcriptomic data showed that the Chol synthesis-related genes and the Chol influx-associated gene, such as _Ldlr_ gene, are downregulated, while the Chol efflux and cholesteryl ester synthesis-associated genes, such as _Aba1_, _Abc31_, _Soat1_, _Soat2_, and _Pla2g12a_, are upregulated in 7 KCh-treated cardiomyocytes (Figure 6). ABCA1 and SOAT appear to play a role in reducing the accumulation of free sterol. Increased PLA2 expression and lysoC accumulation in cardiomyocytes may represent the cellular effort to supply sufficient fatty acids for CE esterification. Taken together, the transcriptomic and metabolic changes may represent a compensatory cytoprotective response of cardiomyocytes to 7 KCh. Moreover, excessive formation of lysophospholipids may have a detrimental effect on cardiomyocytes. Enhanced lysophosphatidylcholine (LPC) production has been associated with apoptotic cardiomyopathy in high-fructose and high-fat-fed animal models [36]. Arachidonyl oxysterol that can be generated by SOAT may act as an apoptotic signal [33]. The relationship involving PLA2, SOAT, and accumulation of lipid metabolites in 7 KCh-treated cardiomyocytes may be more complicated than previously thought. It is plausible that the fine-tuned gene regulatory and metabolic networks exist in cardiomyocytes to ensure proper cellular responses to oxysterols. The destiny of cells may depend on various inputs to these networks (such as oxysterol level and availability of certain metabolites, e.g., PC) and the presence of regulatory elements (such as expression levels of specified genes, e.g., those encoding SOAT and PLA2). The inhibitory effect of 7 KCh on the MVA pathway in cardiomyocytes has been seldom discussed. The MVA pathway plays a key role in a variety of biological processes [11]. In mammalian cells, the MVA pathway is the intracellular source of isopentenyl pyrophosphate (IPP), the precursor of Chol (steroid biosynthesis), famesyl-pyrophosphate, and geranylgeranyl-pyrophosphate, dolichol (N-glycan biosynthesis), and coenzyme Q (ubiquinone biosynthesis) [11]. Chol is an integral component of cellular membranes, the precursor of steroid hormones, vitamin D, and bile acids [11; 37]. Chol depletion impairs cardiac contraction [38]. Dolichol is an essential component of the N-glycosylation of nascent polypeptides in the ER [39; 40]. IPP molecules are used to produce the quinone CoQ. The hydrophobic isoprenoid chain of CoQ is used to localize the mitochondrial inner membrane, where the quinone group serves as an electron carrier and enables ATP production [41; 42]. Reduction in expression of MVA pathway-related genes and the intermediates GPP and FPP suggests a decrease in the flux of the MVA pathway. However, the downstream products such as CoQ and dolichols are only mildly affected. It may be accounted for by upregulation of _Cq2_ and _Dludds_ gene expression, which may represent a compensatory mechanism to maintain CoQ and dolichols under the condition of the reduced flux of the MVA pathway.