Melatonin attenuates vascular calcification by activating autophagy via an AMPK/mTOR/ULK1 signaling pathway.

Melatonin has been demonstrated to protect against calcification in cyclosporine nephrotoxicity. Autophagy may affect vascular calcification by inhibiting apoptosis and the transdifferentiation process. This study sought to explore whether melatonin attenuates vascular calcification by regulating autophagy via the AMP-activated protein kinase/mammalian target of rapamycin/Unc-51-like kinase 1 (AMPK/mTOR/ULK1) signaling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualised by Alizarin red staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure expression of runt-related transcription factor 2 (Runx2, an osteogenic transcription factor), light chain 3 (LC3) II/I, and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were downregulated, whereas LC3 II/I was increased in response to melatonin, and was accompanied by decreased apoptosis. An immunofluorescence assay revealed that melatonin treatment markedly decreased Runx2 expression and upregulated LC3 expression. Treatment with the autophagy inhibitor 3-methyladenine reversed this phenomenon. Melatonin significantly increased expression of p-AMPK and p-ULK1, and decreased mTOR expression. Treatment with compound C (an inhibitor of AMPK) or MHY1485 (an agonist of mTOR) ablated the observed benefits of melatonin treatment. Melatonin protects VSMCs against calcification by activating autophagy via the AMPK/mTOR/ULK1 pathway.

Effects of liraglutide on left ventricular function in patients with non-ST-segment elevation myocardial infarction.

The influence of glucagon-like peptide-1 has been studied in several studies in patients with acute myocardial infarction, but not in patients with non-ST-segment elevation myocardial infarction (NSTEMI). We planned to evaluate the effects of liraglutide on left ventricular function in patients with NSTEMI. A total of 90 patients were randomized 1:1 to receive either liraglutide (0.6 mg for 2 days, 1.2 mg for 2 days, followed by 1.8 mg for 3 days) or placebo for 7 days. Eighty-three patients completed the trial. Transthoracic echocardiography was used to assess left ventricular function. At 3 months, the primary endpoint, the difference in the change in left ventricular ejection fraction between the two groups was +4.7 % (liraglutide vs. placebo 95 % CI +0.7 to +9.2 % P = 0.009) under intention-to-treat analysis. The difference in decrease in serum glycosylated hemoglobin levels was -0.2 % (liraglutide vs. placebo 95 % CI -0.1 to -0.3 %; P < 0.001). Inflammation and oxidative stress improved significantly in the liraglutide group compared to the placebo group. Liraglutide could improve left ventricular function in patients with NSTEMI, making it a potential adjuvant therapy for NSTEMI.