
-   In left ventricular myocardium of adult male Wistar rats, chronic intermittent hypoxia (CIH) increased the total cytosolic-PLA2alpha (cPLA2alpha) protein in cytosol and membranes and phosphorylated-cPLA2alpha in membranes, while downregulating calcium-independent PLA2 and secretory-PLA2IIA. Reactive oxygen species (ROS) are suggested to be responsible for the activation of cPLA2alpha under CIH conditions [PMID: 28459156].
-   Expression of sPLA2-IIa is up-regulated in response to cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and oxidized low-density lipoprotein (LDL) [PMID: 11509445, PMID: 10807743].
-   In nude mice bearing lung cancer tumors with sPLA2 knockdown cells, sPLA2 knockdown reduced NF-kappaB phosphorylation and tumor growth in vivo in part by attenuating NF-kappaB activity [PMID: 23079010].
-   Increased expression of secretory non-pancreatic phospholipase A(2) (sPLA(2)-IIA) could be part of the inflammatory reaction in atherosclerosis. Conditions leading to cell differentiation induced sPLA(2)-IIA expression in human arterial smooth muscle cells in culture (HASMC) and further exposure to IFN-gamma can up-regulat sPLA(2)-IIA transcription and secretion. IFN-gamma-stimulated sPLA(2)-IIA transcription appears to involve the STAT-3 protein [PMID: 10811652].
-   In cultured human vascular endothelial cells stimulated with interleukin-1alpha (IL-1alpha), results suggested the existence of regulatory mechanisms of IL-1alpha-induced PGI2 production, which involve PGHS and PLA2 gene transcription [PMID: 10367586].
-   PLA2G2A is specifically expressed in gastric cancer cell lines with constitutive Wnt activity, implicating beta-catenin-dependent Wnt signaling as a major upstream regulator of PLA2G2A expression. PLA2G2A expression is elevated in primary gastric, colon, and prostate early-stage tumors, but decreases in metastatic and late-stage tumors. There was a strong association between PLA2G2A promoter methylation status and PLA2G2A expression, suggesting that the loss of PLA2G2A expression in late-stage cancers may be due to epigenetic silencing. Among non-PLA2G2A-expressing cell lines, pharmacologic inhibition of epigenetic silencing reactivated PLA2G2A in Wnt-active lines, but in non-Wnt-active lines, a combination of Wnt hyperactivation and inhibition of epigenetic silencing were both required for PLA2G2A reactivation [PMID: 18519687].

## Summary

In heart diseases and toxic events affecting the heart, the upregulation of PLA2G2A, results in increased activity of secretory type II phospholipase A2 (sPLA2-IIA). This enzyme hydrolyzes the sn-2 fatty acid acyl ester bond of phospholipids, releasing free fatty acids and lysophospholipids [CS: 9]. This activity is vital in modulating the phospholipid metabolism in biomembranes and plays a role in inflammatory responses [CS: 8]. The upregulation of PLA2G2A in response to cellular stress and damage in the heart, such as in conditions induced by amiodarone treatment, suggests a defensive response involving altered phospholipid metabolism and cellular repair mechanisms [CS: 7].

The increased sPLA2-IIA activity due to PLA2G2A upregulation has several downstream effects in heart diseases. It amplifies inflammation by producing fatty acids that are precursors to pro-inflammatory eicosanoids [CS: 8]. Conditions like chronic intermittent hypoxia (CIH) lead to an increase in reactive oxygen species (ROS), which activate different forms of PLA2 [CS: 7]. The increased expression of sPLA2-IIa, encoded by PLA2G2A, in response to pro-inflammatory cytokines like IFN-gamma, TNF-alpha, and IL-1beta indicates its involvement in the inflammatory response [CS: 8]. Additionally, the enzyme's action on cellular membranes changes their composition, impacting cell signaling and function in the heart [CS: 6]. This response, while potentially aiding in clearing damaged cells and tissues, can contribute to further inflammation and damage [CS: 7].
