Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS), and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress. mTOR signaling presents both cardioprotective and cardiotoxic effects on the diabetic heart, which interplays with oxidative stress directly or indirectly. Antihyperglycemic agent metformin and newly found free radicals scavengers, Sirt1 and CTRP9, may serve as promising pharmacological therapeutic targets. In this review, we will focus on the role of oxidative stress and mTOR signaling in the pathophysiology of MI/R injury in diabetes and discuss potential mechanisms and their interactions in an effort to provide some evidence for cardiometabolic targeted therapies for ischemic heart disease (IHD).

/pdf/insights-for-oxidative-stress-and-mtor-signaling-in-1p87316n5y.pdf

Insights for Oxidative Stress and mTOR Signaling in Myocardial Ischemia/Reperfusion Injury under Diabetes.

The cardioprotection by ischemic preconditioning is lost in aged wild-type and in STAT3 (signal transducer and activator of transcription 3)-deficient mice. The aim of the present study was to analyze whether or not ischemic postconditioning (iPoco) was effective in aged mice hearts and whether iPoco was dependent on STAT3. Young (3 months) and aged (>13 months) C57Bl6/J mice underwent 30 minutes of ischemia and 2 hours of reperfusion without or with iPoco (3 cycles of 10 seconds of ischemia/10 seconds of reperfusion [3×10] or 5 cycles of 5 seconds of ischemia/5 seconds of reperfusion [5×5] at the beginning of reperfusion). In young mice, both iPoco3×10 and iPoco5×5 reduced infarct size (IS), whereas in aged mice, only iPoco5×5 was effective in reducing IS. In young mice, iPoco3×10 increased the phosphorylated over total STAT3 (phosphorylated STAT3/STAT3) ratio at 10 minutes of reperfusion in the postconditioned anterior wall compared with the control posterior wall. In aged mice hearts, total STAT3 and p...

Cardioprotection by Ischemic Postconditioning Is Lost in Aged and STAT3-Deficient Mice

Pharmacological validation of the chronic mild stress model of depression

Ischemic preconditioning (IPC) or postconditioning (Ipost) is proved to efficiently prevent ischemia/reperfusion injuries. Mortality of diabetic patients with acute myocardial infarction was found to be 2–6 folds higher than that of non-diabetic patients with same myocardial infarction, which may be in part due to diabetic inhibition of IPC- and Ipost-mediated protective mechanisms. Both IPC- and Ipost-mediated myocardial protection is predominantly mediated by stimulating PI3K/Akt and associated GSK-3β pathway while diabetes-mediated pathogenic effects are found to be mediated by inhibiting PI3K/Akt and associated GSK-3β pathway. Therefore, this review briefly introduced the general features of IPC- and Ipost-mediated myocardial protection and the general pathogenic effects of diabetes on the myocardium. We have collected experimental evidence that indicates the diabetic inhibition of IPC- and Ipost-mediated myocardial protection. Increasing evidence implies that diabetic inhibition of IPC- and Ipost-mediated myocardial protection may be mediated by inhibiting PI3K/Akt and associated GSK-3β pathway. Therefore any strategy to activate PI3K/Akt and associated GSK-3β pathway to release the diabetic inhibition of both IPC and Ipost-mediated myocardial protection may provide the protective effect against ischemia/reperfusion injuries.

/pdf/diabetic-inhibition-of-preconditioning-and-postconditioning-4jeqdw2alw.pdf

Diabetic inhibition of preconditioning- and postconditioning-mediated myocardial protection against ischemia/reperfusion injury.

All seven STAT proteins are expressed in the heart, and in this review we will focus on their contribution to cardiac physiology and to ischemic heart disease and its consequences. A substantial literature has focused on the roles of STAT1 and STAT3 in ischemic heart disease, where, at least in the acute phase, they appear to have a yin-yang relationship. STAT1 contributes to the loss of irreplaceable cardiac myocytes both by increasing apoptosis and by reducing cardioprotective autophagy. In contrast, STAT3 is cardioprotective, since STAT3-deficient mice have larger infarcts following ischemic injury, and a number of cardioprotective agents have been shown to act, at least partly, through STAT3 activation. STAT3 is also absolutely required for preconditioning-a process where periods of brief ischemia protect against a subsequent or previous prolonged ischemic episode. Prolonged activation of STAT3, however, is strongly implicated in the post-infarction remodeling of the heart which leads to heart failure, where, possibly together with STAT5, it augments activation of the renin-angiotensin system.

/pdf/stat-transcription-in-the-ischemic-heart-4683y0f195.pdf

STAT transcription in the ischemic heart

Triggering receptor expressed on myeloid cells-2 (TREM2) is a key pro-tumorigenic marker of tumor-infiltrating macrophages, showing potent immunosuppressive activity in tumor microenvironment. A platinum(IV) complex OPA derived from oxaliplatin (OP) and artesunate (ART) exhibited direct cytotoxicity against human colon cancer cells and immunomodulatory activity to inhibit TREM2 on macrophages in vitro  and vivo . Furthermore, OPA deterred the tumor growth in mice models bearing MC38 colorectal tumor by reducing the number of CD206 +  and CX 3 CR1 +  immunosuppressive macrophages; it also promoted the expansion and infiltration of immunostimulatory dendritic, cytotoxic T, and natural killer cells. OPA is the first small-molecular TREM2 inhibitor capable of relieving immunosuppressive tumor microenvironment and enhancing chemical anticancer efficiency of platinum drug, thus showing typical characteristics of a chemoimmunotherapeutic agent.

Platinum-based TREM2 Inhibitor Suppresses Tumor via Remodeling Immunosuppressive Microenvironment.

Ischemic postconditioning (IPC) represents one of the most effective cardioprotective strategies against myocardial ischemia/reperfusion. Depression is commonly present in patients with coronary heart disease. However, whether depression interferes with the cardioprotection of IPC during myocardial ischemia/reperfusion and their underlying mechanisms remain largely unknown. Isolated hearts from chronic mild stress induced-depressed rats and non-depressed rats were subjected to 30 min of regional ischemia followed by 120 min of reperfusion in the presence or absence of IPC (consisting of 6 cycles of 10 s of reperfusion and 10 s of ischemia immediately after the sustained ischemia). Myocardial infarct size, creatine kinase (CK) and cardiac troponin T (cTnT) release, cardiac function and phosphorylated AKT and signal transducer and activator of transcription-3 (STAT-3) were measured. IPC significantly prevented the hearts from myocardial ischemia/reperfusion injury by decreasing infarct size, and CK and cTnT release in coronary effluent, and improving cardiac functional recovery in non-depressed rats. However, these cardioprotective effects of IPC were not observed in depressed rats. In addition, IPC had no effects on the phosphorylation of AKT and STAT-3 at reperfusion in depressed hearts, although it markedly increased the phosphorylation of AKT and STAT-3 at reperfusion in non-depressed hearts. In conclusion, these data indicate that cardioprotection by IPC is abolished during myocardial ischemia/reperfusion in depressed rats, and the underlying mechanisms are probably related to the impaired activation of AKT and STAT-3 at reperfusion.

Cardioprotection by ischemic postconditioning is abolished in depressed rats: role of Akt and signal transducer and activator of transcription-3

This study used a model of ischemia-reperfusion injury to the brachial artery endothelium to investigate whether the protective role of ischemic postconditioning (IPostC) is impaired in patients with major depressive episode. Flow-mediated dilation (FMD) was measured before and after ischemia-reperfusion in the absence or presence of IPostC in 24 patients with major depressive disorder and 20 healthy controls. In addition, the severity of the depression, as assessed by the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) scores, and plasma nitrogen dioxide (NO(x)) levels were also determined. Ischemia-reperfusion resulted in a significant decrease in FMD in both patients with a major depressive episode and healthy controls. IPostC effectively prevented this decrease in FMD in healthy controls, but not in patients with a major depressive episode. HDRS and BDI scores were markedly increased, but plasma NO(x) levels decreased, in patients with a major depressive episode compared with those in healthy controls. Correlation analysis showed that HDRS and BDI scores and plasma NO(x) levels were significantly associated with post-ischemia-reperfusion FMD. These results suggest that endothelial protection by IPostC is impaired in patients with major depressive disorder, which may be related to the decrease in endothelial nitric oxide production and the severity of the depression.

Impairment of endothelial protection by ischemic postconditioning in patients with major depressive disorder.

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Platinum-based TREM2 Inhibitor Suppresses Tumor via Remodeling Immunosuppressive Microenvironment.

Cardioprotection by ischemic postconditioning is abolished in depressed rats: role of Akt and signal transducer and activator of transcription-3

Impairment of endothelial protection by ischemic postconditioning in patients with major depressive disorder.