ABSTRACT
Metformin has been shown to ameliorate diabetic cardiomyopathy. In the present research we investigatedwhether metformin would reduce cardiomyocyte apoptosis that was induced by high-glucose stimulation in vitrovia activation of PP2A. Primary human and rat cardiomyocytes were subject to high-glucose stimulation. Okadaicacid was used to inhibit PP2A activity. Cell viability and apoptosis was assessed using CCK-8 and by flowcytometry, respectively. Release of HMGB1, TNFa or IL-6 was analyzed by ELISA. Oxidative stress wasevaluated by measuring cellular ROS and mitochondrial superoxide level. PP2A activity was evaluated by Serine/Threonine phosphatase assay system or analyzing Y307 phosphorylation level of PP2A catalytic domain (PP2Ac)by Western blot and the association between PP2Ac and a4 by co-immunoprecipitation. Activation of the NF-jBsignaling pathway was assessed by detecting Ser32 phosphorylation level of IjBa as well as nuclear entry of p65protein by Western blot. Activation of the GSK3b/MCL1 signaling pathway was assessed by detecting Ser9phosphorylation level of GSK3b and protein level of MCL1. We found Metformin pre-treatment attenuatedhuman and rat cardiomyocytes apoptosis, HMGB1, TNFa and IL-6 release and ROS production that were inducedby high-glucose stimulation, and these effects of metformin could be blocked by okadaic acid treatment. Metformin reduced the upregulation of PP2Ac pY307 and the PP2Ac-a4 association, which was not affected byokadaic acid treatment. Metformin pre-treatment reduced NF-jB activation in human and rat cardiomyocytesapoptosis that was elicited by high-glucose stimulation, and this effect of metformin could be blocked by okadaicacid treatment. GSK3b/MCL1 is not part of metformin activating PP2A induced myocardial cell death inhibition.In conclusion, metformin reduced apoptosis, ROS production and inflammatory response in primary human andrat cardiomyocytes in vitro in a PP2A dependent manner.
ABSTRACT
@#Objective To compare the in-hospital and midterm outcomes after simultaneous hybrid coronary revascularization (HCR) with off-pump coronary artery bypass grafting (OPCAB) in diabetic patients with multivessel coronary artery disease. Methods One hundred thirty-two diabetic patients with multivessel coronary artery disease underwent one-stop HCR at Fuwai Hospital from January 2010 to January 2015. These patients were 1∶2 matched with those who underwent OPCAB using propensity score matching. Results Simultaneous HCR had less chest tube drainage (618 (420, 811) ml vs. 969 (711, 1 213)ml, P<0.001), lower transfusion rate (19.7% vs. 34.1%, P=0.026), shorter mechanical ventilation time (11.6 (8.2, 14.8) h vs. 16.0 (12.1, 18.7) h, P<0.001), and shorter stay in intensive care unit (21.5 (18.8, 42.0) h vs. 44.6 (23.7, 70.1) h, P<0.001) than OPCAB. During over median 40 months follow-up, simultaneous HCR offered similar major adverse cardiac or cerebrovascular events (MACCE) rate (6.8% vs 9.0%, P=0.826), but lower stroke rate (0%vs 3.0%, P=0.029), compared with OPCAB. Conclusion For selected patients with diabetes, simultaneous HCR provides a safe and effective revascularization alternative. It decreases perioperative invasiveness and incurred similar and favorable midterm outcomes with OPCAB.