Aspirin Enhances the Protection of Hsp90 from Heat-Stressed Injury in Cardiac Microvascular Endothelial Cells Through PI3K-Akt and PKM2 Pathways

Abstract

Heat stress (HS) often causes sudden death of humans and animals due to heart failure, mainly resulting from the contraction of cardiac microvasculature followed by myocardial ischemia. Cardiac microvascular endothelial cells (CMVECs) play an important role in maintaining vasodilatation. Aspirin (ASA) is well known for its protective abilities of febrile animals. However, there is little knowledge about molecular resistance mechanisms of CMVECs and which role ASA may play in this context. Therefore, we used a heat stress model of rat cardiac microvascular endothelial cell cultures in vitro and investigated the cell injuries and molecular resistance mechanism of CMVECs caused by heat stress, and the effect of aspirin (ASA) on it. HS induced severe pathological damage of CMVECs and cellular oxidative stress and dysfunction of NO release. Hsp90 was proven to be indispensable for resisting HS-injury of CMVECs through PI3K-Akt and PKM2 signaling pathways. Meanwhile, PKM2 functioned in reducing Akt phosphorylation. ASA treatment of CMVECs induced a significant expression of Hsp90, which promoted both Akt and PKM2 signals, which are beneficial for relieving HS damage and maintaining the function of CMVECs. Akt activation also promoted HSF-1 that regulates the expression of Hsp70, which is known to assist Hsp90′s molecular chaperone function and when released to the extracellular liquid to protect myocardial cells from HS damage. To the best of our knowledge, this is the first study to show that HS damages CMVECs and the protection mechanism of Hsp90 on it, and that ASA provides a new potential strategy for regulating cardiac microcirculation preventing HS-induced heart failure.

Acetylsalicylic acid and salicylic acid present anticancer properties against melanoma by promoting nitric oxide-dependent endoplasmic reticulum stress and apoptosis

“…This activation involves both mTOR complexes, mTORC1 and mTORC2, as evaluated by means of the phosphorylation of specific substrates of each complex. Additionally, we found that the upstream effector of mTORC1 and downstream effector of mTORC2, Akt 55 , is also activated upon SA and ASA treatment, which is in accordance to some recently published results 56 . Usually, Akt activation is also related to cell survival due to its antiapoptotic effects 57 .…”

Mechanism overview and target mining of atherosclerosis: Endothelial cell injury in atherosclerosis is regulated by glycolysis (Review)

“…Following phosphorylation, PKM2 is converted to a dimer, promoting the upstream glycolytic products of PK to enter the biosynthetic pathway ( 74 ). In addition, the expression of PKM2 is differentially regulated by the PI3K/AKT signal-ling pathway ( 75 ). PKM2-regulated glycolysis contributes to the proliferation and migration of vascular smooth muscle cells, and is positively correlated with AS development ( 12 ).…”

Thermal stress induces dysfunction and facilitates senescence via disruption of cytoskeletal rearrangement and stimulation of the inflammatory response in primary endothelial cells

“…Increasing evidence shows that the vascular system is acutely damaged by severe burns, resulting in prolonged hospitalization (Romero et al 2018). A recent study showed that exposure to 43°C for a few hours can cause the upregulation of heat shock proteins and irreversible cellular membrane disruption in cardiac microvascular ECs (Zhang et al 2020b).…”

“…Many in vitro studies have revealed that cellular damage caused by TS is dependent on the temperature and length of exposure (Log 2017). A recent report demonstrated that TS induced an upregulation of Hsp90 through the PI3K-Akt and PKM2 pathways in cardiac microvascular ECs (Zhang et al 2020a).…”