Hydrolysis of lipoproteins by sPLA2’s enhances mitogenesis and eicosanoid release from vascular smooth muscle cells: Diverse activity of sPLA2’s IIA, V and X

Discovery of a Series of Indole-2 Carboxamides as Selective Secreted Phospholipase A2 Type X (sPLA2-X) Inhibitors

“…2 However, an in vivo study in a mouse model of atherosclerosis has shown that expression of sPLA 2 -X in bone marrow cells limits the development of atherosclerosis. 11 Additionally, the VISTA-16 (Vascular Inflammation Suppression to Treat Acute Coronary Syndrome) phase III trial showed that administration of varespladib methyl did not reduce the occurrence of acute coronary syndrome (ACS) events but significantly increased the risk of nonfatal myocardial infarction. 12 These results could indicate that a broad spectrum sPLA 2 inhibitor may be detrimental in atherosclerotic cardiovascular disease.…”

“…In vitro and in vivo studies have reported pro-atherogenic properties of sPLA 2 -X comprising lipoprotein modifications leading to foam cell formation, reduced cell cholesterol efflux, altered immune cells maturation, and vascular cells proliferation. − These effects indicate that sPLA 2 -X is a potential novel therapeutic target for the treatment of cardiovascular diseases . However, an in vivo study in a mouse model of atherosclerosis has shown that expression of sPLA 2 -X in bone marrow cells limits the development of atherosclerosis . Additionally, the VISTA-16 (Vascular Inflammation Suppression to Treat Acute Coronary Syndrome) phase III trial showed that administration of varespladib methyl did not reduce the occurrence of acute coronary syndrome (ACS) events but significantly increased the risk of nonfatal myocardial infarction .…”

“…An initial attempt of functionalizing the indole core by N-benzylation instead of N-arylation proved counterproductive as well (9, Table 1). Replacement of the carboxylic acid group by a primary amide (10) yielded a complete loss of inhibition, while an acylsulfonamide bioisosteric element (11) was tolerated albeit with a 5-fold reduction in potency, indicating specific spatial and electronic restraints for the coordination of the calcium ion. Having identified 5 as a promising sPLA 2 -X inhibitor, we assessed the importance of the indole system (see Table S1 in the Supporting Information).…”

High sPLA2-IIA level is associated with eicosanoid metabolism in patients with bacterial sepsis syndrome

“…The pathophysiological mechanism of sepsis is complex and is still not fully understood [1,39]. The role of sPLA2-IIA has been described extensively in other inflammatory diseases, such as atherosclerosis [40], lung cancer [41], ocular surface drought [42], rheumatoid arthritis [43] and neurodegenerative diseases [44]. In addition, sPLA2-IIA has bactericidal activity [45,46].…”

Harmful and protective roles of group V phospholipase A2: Current perspectives and future directions

“…In vitro studies showed that these modifications were likely due to the capacity of Pla2g5 to modify LDL and induce foam cell formation [61] through Syndecan 4 (a proteoglycan receptor) uptake [64]. Additionally, hydrolysis of LDL and HDL by PLA2G5 could generate pro-atherogenic products acting on smooth muscle cells [65]. Accordingly, a recent report showed that hydrolysis of phospholipids in LDL is accomplished by several PLA 2 s, PLA2G10, PLA2G3, PLA2G2F, PLA2G2A, and PLA2G5.…”