Table 1.

Cardioprotective and cardiotoxic effects of mTOR signaling in MI/R injury under diabetes.

Effect of mTOR	Study	Animal model	Interventions	Outcomes
Cardioprotective	Glazer et al. [67]	Transgenic mice	Overexpression of cardiac mTOR	Overexpression of cardiac mTOR reduced mortality in the acute phase and preserved cardiac function in the chronic phase after transient ischemia in vivo
Cardioprotective	Land and Tee [68]	Transgenic mice	Overexpression of cardiac mTOR	mTOR-Tg mice performed better cardiac function recovery and had less of the necrotic markers CK and LDH subjected to I/R injury in high fat diet-induced obesity
Cardioprotective	Park et al. [69]	Diabetic mice induced by STZ	Rapamycin (5 mg/kg i.v.) 10 min before I/R	Lin28a overexpression increased p-mTOR and p-p70s6k expression in myocardium exposed to I/R injury in diabetic mice while inhibition of mTOR reduced Lin28a's cardioprotective effects
Cardioprotective	Schenkel et al. [70]	C57BL/6 mice	Torin1 (i.p.) immediately after MI with a short 2-day follow-up treatment to inhibit both mTORC1 and mTORC2 Rictor and Raptor siRNA (i.v.) to selectively inhibit mTORC1 or mTORC2 PRAS40 siRNA (i.v.) to inhibit mTOR1	Inhibition of both mTORC1 and mTORC2 with Torin1 led to increased cardiomyocyte apoptosis and tissue damage after MI. Predominant mTORC1 signaling by suppression of mTORC2 similarly increased cardiomyocyte apoptosis and tissue damage after myocardial infarction. In comparison, preferentially shifting toward mTORC2 signaling by inhibition of mTORC1 with PRAS40 led to decreased cardiomyocyte damage after MI
Cardioprotective	Tanguy et al. [50]	Neonatal rat ventricular cardiomyocytes	Rapamycin: 50 nM Adenovirus overexpressing mTOR	Inhibition of mTOR by rapamycin antagonized high glucose-induced inhibition of autophagy and enhanced cardiomyocyte death, while adenovirus-mediated overexpression of mTOR was sufficient to block autophagic flux regardless of glucose concentrations
Cardioprotective	Rajapakse et al. [71]	Human umbilical vein endothelial cells (HUVECs)	Rapamycin: 25 nM	mTOR activation enhances the activity of HIF1α by inhibiting proteolytic degradation, resulting in elevated VEGF expression
Cardioprotective	Chong et al. [72]	Human endothelial cells	Rapamycin: 5–10 ng/mL	Loss of mTOR blocks endothelial proliferation and angiogenesis as well as the proliferation of endothelial progenitor cells ex vivo
Cardiotoxic	Yao et al. [73]	APN knockout mice	Rapamycin (2 mg/kg, i.p.)	Rapamycin reversed APN deficiency-induced drop of fat oxidation in high fat diet feeding
Cardiotoxic	Si et al. [74]	Transgenic mice	Conditional mTOR knockout mice	Inhibition of mTORC1 reduced endoplasmic reticulum stress, thereby reducing cardiomyocytes death
Cardiotoxic	Lemaître et al. [75]	CD-1 mice	Rapamycin (0.25 mg/kg, i.p.)	Inhibition of mTOR by rapamycin before ischemia reduced I/R-induced myocardial infarction via activating the JAK2 signal transducer and activator of transcription 3 (STAT3) signaling pathway
Cardiotoxic	Fourcade et al. [76]	Transgenic mice	Cardiac-specific knockout Raptor to inhibit mTORC1 in vivo	In cardiac mTORC1 disrupted mice, fatty acid oxidation is significantly decreased, whereas glucose oxidation is increased subjected to transverse aortic constriction (TAC)
Cardiotoxic	Maiese et al. [77]	Male WKY rats and HUVECs	Recombinant adenoviral (rAd) expressing short hairpin RNA (shRNA), S6K1 to inhibit mTORC1	Inhibition of mTORC1/S6K1 signaling protected endothelial dysfunction related to eNOS uncoupling in vivo and in vitro
Cardiotoxic	Wang et al. [78]	AMPKα2 knockout mice	Metformin (100 mg/kg/day, gavage) for 3 weeks	Administration of metformin was effective in attenuating TAC-induced LV remodeling in both wild-type and AMPKα2 knockout mice and reduced p-mTOR at Ser2448 and its downstream target p-p70S6K at Thr389