Novel cardioprotective mechanism for Empagliflozin in nondiabetic myocardial infarction with acute hyperglycemia

Autosis as a selective type of cell death

“…Autosis induced by oncolytic virus-infected T cells is a potent bystander-killing form for tumor cells but not for non-tumor cells (Zheng et al, 2022). Tat-BECN1 peptide is an autophagy inducer (Shoji-Kawata et al, 2013;He et al, 2022a) and a potent autosis inducer upon high dosage or prolonged treatment (Liu et al, 2013;Zhang et al, 2018;Zhang et al, 2019;Fernandez et al, 2020;Nah et al, 2020;Deng et al, 2022;Nah et al, 2022;Zheng et al, 2022). Tat-BECN1 and derivatives not only induce autosis specifically in HIV-1-infected cells (Zhang et al, 2018;Zhang et al, 2019) but also kill cancer cells in culture in vitro and inhibit tumor xenograft growth with negligible systemic toxicity in vivo (Wang et al, 2015;Ding et al, 2018;Zhou et al, 2019).…”

“…Autosis is autophagy-dependent as downregulation of core autophagy machinery leads to inhibition of autotic cell death, which includes manipulating 1) initiation step, by deletion of ULK1 complex subunit ULK1 (Nah et al, 2020) or ATG13 (Liu et al, 2013); 2) nucleation step, by deletion of Class III PI3K complex subunit Beclin 1 (Liu et al, 2013;Liao et al, 2016;Nah et al, 2020;Deng et al, 2022;Jiang et al, 2022) or ATG14 (Liu et al, 2013), or by administration of inhibitors 3-methyladenine (3-MA) (Liu et al, 2013;Nah et al, 2020) or PIK-III (Zheng et al, 2022); and 3) elongation step, by deletion of ATG5 (Liu et al, 2013;Zhang et al, 2018;Zhang et al, 2019) or ATG7 (Liu et al, 2013;Zhang et al, 2018;Zhang et al, 2019;Koenig et al, 2020;Nah et al, 2020;Nah et al, 2022;Yin et al, 2022). Blocking the maturation of autophagosomes to autolysosomes by bafilomycin A1 (Liu et al, 2013;Zhang et al, 2018;Zhang et al, 2019;Nah et al, 2020) does not attenuate autosis, suggesting that the later step of autophagy is not required.…”

“…Na + /K + -ATPase antagonist cardiac glycosides were identified as autosis inhibitors via high-throughput chemical screening (Liu et al, 2013). Several cardiac glycosides have been shown to be protective against autosis, including digoxin (Liu et al, 2013;Chen et al, 2016;Zhang et al, 2018;Zhang et al, 2019;Camuzard et al, 2020;Fernandez et al, 2020;Deng et al, 2022;Yin et al, 2022), neriifolin (in vivo during cerebral H/I) (Liu et al, 2013;Fernandez et al, 2020), ouabain (in vivo during renal and cardiac I/R) (Fernandez et al, 2020;Nah et al, 2020), digitoxigenin (Liu et al, 2013;Chen et al, 2016), and strophanthidin (Liu et al, 2013). Downregulation of Na + /K + -ATPase alpha subunit ATP1A1 inhibits autosis in various cell lines (Liu et al, 2013;Zhang et al, 2018;Zhang et al, 2019;Nah et al, 2020;Zheng et al, 2022).…”

“…Homocysteine and copper co-treatment induces apoptosis and autosis in cardiomyocytes, which is p62-dependent (Yin et al, 2022). Empagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces autosis in cardiomyocytes in a Beclin 1-dependent manner (Deng et al, 2022;Jiang et al, 2022).…”

Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms

“…In fact, the inhibitory effect of SGLT2i on NHE1 has been widely demonstrated [163], but it is not clear whether Beclin1 is a downstream target of NHE1. Deng et al [164] found that Beclin1 but not NHE1 was targeted by empagliflozin. Empagliflozin was shown to inhibit the increase in autophagy caused by myocardial infarction with acute hyperglycaemia.…”