GDF11 inhibits cardiomyocyte pyroptosis and exerts cardioprotection in acute myocardial infarction mice by upregulation of transcription factor HOXA3.

NLRP3 (Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3) inflammasome-mediated cardiomyocytes pyroptosis plays a crucial part in progression of acute myocardial infarction (MI). GDF11 (Growth Differentiation Factor 11) has been reported to generate cytoprotective effects in phylogenesis and multiple diseases, but the mechanism that GDF11 contributes to cardioprotection of MI and cardiomyocytes pyroptosis remains poorly understood. In our study, we first determined that GDF11 was abnormally downregulated in the heart tissue of MI mice and hypoxic cardiomyocytes. Moreover, AAV9-GDF11 markedly alleviated heart function in MI mice. Meanwhile, GDF11 overexpression also decreased the pyroptosis of hypoxic cardiomyocytes. PROMO and JASPAR prediction software found that transcription factor HOXA3 was predicted as an important regulator of NLRP3, and was confirmed by ChIP assay. Further analysis identifying GDF11 promoted the Smad2/3 pathway resulted in HOXA3 overexpression. Taken together, our study implies that GDF11 prevents cardiomyocytes pyroptosis via HOXA3/NLRP3 signaling pathway in MI mice.

miR-150 regulates glucose utilization through targeting GLUT4 in insulin-resistant cardiomyocytes.

MicroRNAs (miRNAs) play an important role in cardiac function and metabolism. However, whether they regulate insulin resistance (IR) of cardiomyocytes remains unclear. The aim of the present study was to shed light on this issue with a focus on miR-150. We found here that miR-150 level was elevated in myocardium of type 2 diabetes mellitus (T2DM) rat model and in insulin-resistant cardiomyocytes induced by high glucose (25 mM) and high insulin (1 µM). Deregulation of miR-150 downregulated the protein and mRNA levels of glucose transporter 4 (GLUT4) as assessed by western blot, real-time polymerase chain reaction (qPCR), and immunofluorescence assays. Overexpression of miR-150 inhibited glucose utilization in cardiomyocytes as detected by 2-deoxyglucose transport and glucose consumption assays. In contrast, knockdown of miR-150 significantly increased glucose uptake in cardiomyocytes. Moreover, GLUT4 translocation was increased after transfection of miR-150 inhibitor (AMO-150). Collectively, miR-150 reduced glucose utilization by directly decreasing the expression and translocation of GLUT4 in the cardiomyocytes with IR and therefore might be a new therapeutic target for metabolic diseases such as T2DM.

Endothelial to mesenchymal transition contributes to nicotine-induced atherosclerosis.

Rationale: Nicotine exposure via cigarette smoking is strongly associated with atherosclerosis. However, the underlying mechanisms remain poorly understood. The current study aimed to identify whether endothelial to mesenchymal transition (EndMT) contributes to nicotine-induced atherosclerosis. Methods: ApoE-/- mice were administered nicotine in their drinking water for 12 weeks. The effects of nicotine on EndMT were determined by immunostaining on aortic root and RNA analysis in aortic intima. In vitro nicotine-treated cell model was established on human aortic endothelial cells (HAECs). The effects of nicotine on the expression of EndMT-related markers, ERK1/2 and Snail were quantified by real-time PCR, western blot and immunofluorescent staining. Results: Nicotine treatment resulted in larger atherosclerotic plaques in ApoE-/- mice. The vascular endothelial cells from nicotine-treated mice showed mesenchymal phenotype, indicating EndMT. Moreover, nicotine-induced EndMT process was accompanied by cytoskeleton reorganization and impaired barrier function. The α7 nicotine acetylcholine receptor (α7nAChR) was highly expressed in HAECs and its antagonist could effectively relieve nicotine-induced EndMT and atherosclerotic lesions in mice. Further experiments revealed that ERK1/2 signaling was activated by nicotine, which led to the upregulation of Snail. Blocking ERK1/2 with inhibitor or silencing Snail by small interfering RNA efficiently preserved endothelial phenotype upon nicotine stimulation. Conclusion: Our study provides evidence that EndMT contributes to the pro-atherosclerotic property of nicotine. Nicotine induces EndMT through α7nAChR-ERK1/2-Snail signaling in endothelial cells. EndMT may be a therapeutic target for smoking-related endothelial dysfunction and cardiovascular disease.