Hypertrophic preconditioning attenuates post-myocardial infarction injury through deacetylation of isocitrate dehydrogenase 2.

Ischemic preconditioning induced by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischemic insult. In this study we investigated whether a short-term nonischemic stimulation of hypertrophy renders the heart resistant to subsequent ischemic injury. Male mice were subjected to transient transverse aortic constriction (TAC) for 3 days followed aortic debanding on D4 (T3D4), as well as ligation of the left coronary artery to induce myocardial infarction (MI). The TAC preconditioning mice showed markedly improved contractile function and significantly reduced myocardial fibrotic area and apoptosis following MI. We revealed that TAC preconditioning significantly reduced MI-induced oxidative stress, evidenced by increased NADPH/NADP ratio and GSH/GSSG ratio, as well as decreased mitochondrial ROS production. Furthermore, TAC preconditioning significantly increased the expression and activity of SIRT3 protein following MI. Cardiac-specific overexpression of SIRT3 gene through in vivo AAV-SIRT3 transfection partially mimicked the protective effects of TAC preconditioning, whereas genetic ablation of SIRT3 in mice blocked the protective effects of TAC preconditioning. Moreover, expression of an IDH2 mutant mimicking deacetylation (IDH2 K413R) in cardiomyocytes promoted myocardial IDH2 activation, quenched mitochondrial reactive oxygen species (ROS), and alleviated post-MI injury, whereas expression of an acetylation mimic (IDH2 K413Q) in cardiomyocytes inactivated IDH2, exacerbated mitochondrial ROS overload, and aggravated post-MI injury. In conclusion, this study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Therapeutic strategies targeting IDH2 are promising treatment approaches for cardiac ischemic injury.

Mammalian target of rapamycin inhibition attenuates myocardial ischaemia-reperfusion injury in hypertrophic heart.

Pathological cardiac hypertrophy aggravated myocardial infarction and is causally related to autophagy dysfunction and increased oxidative stress. Rapamycin is an inhibitor of serine/threonine kinase mammalian target of rapamycin (mTOR) involved in the regulation of autophagy as well as oxidative/nitrative stress. Here, we demonstrated that rapamycin ameliorates myocardial ischaemia reperfusion injury by rescuing the defective cytoprotective mechanisms in hypertrophic heart. Our results showed that chronic rapamycin treatment markedly reduced the phosphorylated mTOR and ribosomal protein S6 expression, but not Akt in both normal and aortic-banded mice. Moreover, chronic rapamycin treatment significantly mitigated TAC-induced autophagy dysfunction demonstrated by prompted Beclin-1 activation, elevated LC3-II/LC3-I ratio and increased autophagosome abundance. Most importantly, we found that MI/R-induced myocardial injury was markedly reduced by rapamycin treatment manifested by the inhibition of myocardial apoptosis, the reduction of myocardial infarct size and the improvement of cardiac function in hypertrophic heart. Mechanically, rapamycin reduced the MI/R-induced iNOS/gp91phox protein expression and decreased the generation of NO and superoxide, as well as the cytotoxic peroxynitrite. Moreover, rapamycin significantly mitigated MI/R-induced endoplasmic reticulum stress and mitochondrial impairment demonstrated by reduced Caspase-12 activity, inhibited CHOP activation, decreased cytoplasmic Cyto-C release and preserved intact mitochondria. In addition, inhibition of mTOR also enhanced the phosphorylated ERK and eNOS, and inactivated GSK3ß, a pivotal downstream target of Akt and ERK signallings. Taken together, these results suggest that mTOR signalling protects against MI/R injury through autophagy induction and ERK-mediated antioxidative and anti-nitrative stress in mice with hypertrophic myocardium.

Endoplasmic reticulum stress/autophagy pathway is involved in diabetes-induced neuronal apoptosis and cognitive decline in mice.

Diabetes mellitus is a significant global public health problem depicting a rising prevalence worldwide. As a serious complication of diabetes, diabetes-associated cognitive decline is attracting increasing attention. However, the underlying mechanisms are yet to be fully determined. Both endoplasmic reticulum (ER) stress and autophagy have been reported to modulate neuronal survival and death and be associated with several neurodegenerative diseases. Here, a streptozotocin-induced diabetic mouse model and primary cultured mouse hippocampal neurons were employed to investigate the possible role of ER stress and autophagy in diabetes-induced neuronal apoptosis and cognitive impairments, and further explore the potential molecular mechanisms. ER stress markers GRP78 and CHOP were both enhanced in diabetic mice, as was phosphorylation of PERK, IRE1α, and JNK. In addition, the results indicated an elevated level of autophagy in diabetic mice, as demonstrated by up-regulated expressions of autophagy markers LC3-II, beclin 1 and down-regulated level of p62, and increased formation of autophagic vacuoles and LC3-II aggregates. Meanwhile, we found that these effects could be abolished by ER stress inhibitor 4-phenylbutyrate or JNK inhibitor SP600125 in vitro. Furthermore, neuronal apoptosis of diabetic mice was attenuated by pretreatment with 4-phenylbutyrate, while aggravated by application of inhibitor of autophagy bafilomycin A1 in vitro. These results suggest that ER stress pathway may be involved in diabetes-mediated neurotoxicity and promote the following cognitive impairments. More important, autophagy was induced by diabetes possibly through ER stress-mediated JNK pathway, which may protect neurons against ER stress-associated cell damages.

Hypertrophied myocardium is vulnerable to ischemia/reperfusion injury and refractory to rapamycin-induced protection due to increased oxidative/nitrative stress.

Left ventricular hypertrophy (LVH) is causally related to increased morbidity and mortality following acute myocardial infarction (AMI) via still unknown mechanisms. Although rapamycin exerts cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury in normal animals, whether rapamycin-elicited cardioprotection is altered in the presence of LVH has yet to be determined. Pressure overload induced cardiac hypertrophied mice and sham-operated controls were exposed to AMI by coronary artery ligation, and treated with vehicle or rapamycin 10 min before reperfusion. Rapamycin produced marked cardioprotection in normal control mice, whereas pressure overload induced cardiac hypertrophied mice manifested enhanced myocardial injury, and was refractory to rapamycin-elicited cardioprotection evidenced by augmented infarct size, aggravated cardiomyocyte apoptosis, and worsening cardiac function. Rapamycin alleviated MI/R injury via ERK-dependent antioxidative pathways in normal mice, whereas cardiac hypertrophied mice manifested markedly exacerbated oxidative/nitrative stress after MI/R evidenced by the increased iNOS/gp91phox expression, superoxide production, total NO metabolites, and nitrotyrosine content. Moreover, scavenging superoxide or peroxynitrite by selective gp91phox assembly inhibitor gp91ds-tat or ONOO- scavenger EUK134 markedly ameliorated MI/R injury, as shown by reduced myocardial oxidative/nitrative stress, alleviated myocardial infarction, hindered cardiomyocyte apoptosis, and improved cardiac function in aortic-banded mice. However, no additional cardioprotective effects were achieved when we combined rapamycin and gp91ds-tat or EUK134 in ischemic/reperfused hearts with or without LVH. These results suggest that cardiac hypertrophy attenuated rapamycin-induced cardioprotection by increasing oxidative/nitrative stress and scavenging superoxide/peroxynitrite protects the hypertrophied heart from MI/R.

Serum selenium level and gestational diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: The association between serum selenium level and gestational diabetes mellitus (GDM) is controversial. The aim of our study was to systematically review available literature linking selenium to GDM for a comprehensive understanding of the relationship between serum selenium level and GDM in human. METHODS: PubMed, The Cochrane Library and Medline were searched for studies published up to August 2016. Manual searches of references of the relevant original studies were carried out. Pooled estimates were measured using the fixed or random effect model. Overall effect was reported in a standard mean difference (SMD). All data were analyzed with Review Manager 5.3 and Stata 12.0. RESULTS: Of 44 references reviewed, seven studies involving 569 patients met our inclusion criteria and contributed to meta-analysis. All the studies were used to evaluate the relationship between serum selenium level and GDM. Selenium level was significantly lower in women with GDM than those without GDM (SMD = -1.17; 95 % CI: -1.98 to -0.35, P = 0.005). Subgroup analysis showed that such trend was consistent within the non-Caucasian population (Asia: SMD = -2.82; 95 % CI: -5.21 to -0.43, P = 0.02; Africa: SMD = -0.56; 95 % CI: -1.07 to -0.05, P = 0.03) and in the third trimester (SMD = -1.78; 95 % CI: -3.04 to -0.52, P = 0.006), but not within the Caucasian population (Europe: SMD = -0.6; 95 % CI: -1.98 to 0.78, P = 0.39) or in the second trimester (SMD = -0.68; 95 % CI: -1.6 to 0.25, P = 0.15). CONCLUSIONS: The available evidences suggested that serum selenium level was lower in women with GDM than those with normal glucose tolerance, especially within the non-Caucasian population and in the third trimester. However, well-designed prospective studies are needed to understand dynamic associations between selenium status and GDM risk.

Alpha 7 nicotinic acetylcholine receptor agonist GTS-21 mitigates isoflurane-induced cognitive impairment in aged rats.

BACKGROUND: Postoperative cognitive dysfunction is increasingly recognized as an important clinical syndrome. Inhalation anesthetics are commonly used during surgery, and it has been proposed that inhalation anesthetics impair cognitive function. However, there are few clinical interventions and treatments available to prevent this disorder. GTS-21, a selective agonist of alpha 7 nicotinic acetylcholine receptor, has been indicated to exert neuroprotective effects in the experimental animal models of neurodegenerative diseases. Therefore, we hypothesized that pretreatment with GTS-21 attenuates isoflurane-induced cognitive decline in aged rats. METHODS: In the present study, 20-mo-old rats were administered GTS-21 or an equal volume of saline by intraperitoneal injection 30 min before exposure to isoflurane. Then the rats were exposed to 1.3% isoflurane for 4 h. Spatial learning and memory of the rats were assessed at 2 wk after isoflurane exposure. The expression levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α in the hippocampus and cerebral cortex were determined by enzyme-linked immunosorbent assay. Simultaneously, neuronal apoptosis in the hippocampus was also observed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and Nissl staining. RESULTS: We found that exposure to isoflurane induces learning and memory deficits of old rats. IL-1ß in the hippocampus was increased at 4 h after isoflurane exposure. Isoflurane also increased neuroapoptosis in the hippocampus and decreased neuronal density in the CA1 region. And GTS-21 pretreatment effectively alleviated these changes. CONCLUSIONS: The study demonstrated that pretreatment with α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates isoflurane-induced learning and memory impairment in aged rats.

AIM2 Deficiency Alleviates Cardiac Inflammation and Hypertrophy in HFD/STZ-Induced Diabetic Mice by Inhibiting the NLRC4/IRF1 Signaling Pathway.

Absent in melanoma 2(AIM2) exacerbates atherosclerosis by inflammasome assembly. However, AIM2-mediated inflammation in diabetic cardiomyopathy remains incompletely understood. Here we investigate the role of AIM2 in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. By RNA-seq, we found that AIM2 were significantly upregulated in HG-induced macrophages, upregulation of AIM2 in cardiac infiltrating macrophages was confirmed in a high-fat diet (HFD)/streptozotocin (STZ)-induceddiabetic mouse model . Therefore, AIM2 knockout mice were constructed. Compared to WT mice, HFD/STZ-induced cardiac hypertrophy and dysfunction were significantly improved in AIM2-/- mice, despite no changes in blood glucose and body weight. Further, AIM2 deficiency inhibited cardiac recruitment of M1-macrophages and cytokine production. Mechanistically, AIM2-deficient macrophgaes reduced IL-1ß and TNF-α secretion, which impaired the NLRC4/IRF1 signaling in cardiomyocytes, and reduced further recruitment of macrophages, attenuated cardiac inflammation and hypertrophy, these effects were confirmed by silencing IRF1 in WT mice, and significantly reversed by overexpression of IRF1 in AIM2-/- mice. Taken together, our findings suggest that AIM2 serves as a novel target for the treatment of diabetic cardiomyopathy.