ABSTRACT
BACKGROUND: Visceral adipose tissue in individuals with obesity is an independent cardiovascular risk indicator. However, it remains unclear whether adipose tissue influences common cardiovascular diseases, such as atherosclerosis, through its secreted exosomes. METHODS: The exosomes secreted by adipose tissue from diet-induced obesity mice were isolated to examine their impact on the progression of atherosclerosis and the associated mechanism. Endothelial apoptosis and the proliferation and migration of vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque were evaluated. Statistical significance was analyzed using GraphPad Prism 9.0 with appropriate statistical tests. RESULTS: We demonstrate that adipose tissue-derived exosomes (AT-EX) exacerbate atherosclerosis progression by promoting endothelial apoptosis, proliferation, and migration of VSMCs within the plaque in vivo. MicroRNA-132/212 (miR-132/212) was detected within AT-EX cargo. Mechanistically, miR-132/212-enriched AT-EX exacerbates palmitate acid-induced endothelial apoptosis via targeting G protein subunit alpha 12 and enhances platelet-derived growth factor type BB-induced VSMC proliferation and migration by targeting phosphatase and tensin homolog in vitro. Importantly, melatonin decreases exosomal miR-132/212 levels, thereby mitigating the pro-atherosclerotic impact of AT-EX. CONCLUSION: These data uncover the pathological mechanism by which adipose tissue-derived exosomes regulate the progression of atherosclerosis and identify miR-132/212 as potential diagnostic and therapeutic targets for atherosclerosis.
Subject(s)
Apoptosis , Atherosclerosis , Cell Movement , Cell Proliferation , Disease Models, Animal , Disease Progression , Exosomes , Mice, Inbred C57BL , MicroRNAs , Muscle, Smooth, Vascular , Myocytes, Smooth Muscle , Plaque, Atherosclerotic , Animals , MicroRNAs/metabolism , MicroRNAs/genetics , Exosomes/metabolism , Exosomes/pathology , Atherosclerosis/metabolism , Atherosclerosis/pathology , Atherosclerosis/genetics , Cell Proliferation/drug effects , Apoptosis/drug effects , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Myocytes, Smooth Muscle/drug effects , Cell Movement/drug effects , Muscle, Smooth, Vascular/pathology , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/drug effects , Male , Signal Transduction , Cells, Cultured , Obesity/metabolism , Obesity/pathology , Mice, Knockout, ApoE , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelial Cells/drug effects , Aortic Diseases/pathology , Aortic Diseases/metabolism , Aortic Diseases/genetics , Becaplermin/pharmacology , Becaplermin/metabolism , Intra-Abdominal Fat/metabolism , Intra-Abdominal Fat/pathology , Mice , HumansABSTRACT
Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.
Subject(s)
Autophagy , Cold Temperature , Exosomes , Mice, Inbred C57BL , MicroRNAs , Osteogenesis , Animals , Autophagy/drug effects , Mice , Exosomes/metabolism , MicroRNAs/metabolism , MicroRNAs/genetics , Osteogenesis/drug effects , Mesenchymal Stem Cells/metabolism , Osteoporosis/pathology , Cell Differentiation/drug effects , Bone and Bones/metabolism , Female , Bone Density , Sirolimus/pharmacologyABSTRACT
Peptidylarginine deiminases (PADs) are a group of enzymes that catalyze post-translational modifications of proteins by converting arginine residues into citrullines. Among the five members of the PAD family, PAD2 and PAD4 are the most frequently studied because of their abundant expression in immune cells. An increasing number of studies have identified PAD2 as an essential factor in the pathogenesis of many diseases. The successes of preclinical research targeting PAD2 highlights the therapeutic potential of PAD2 inhibition, particularly in sepsis and autoimmune diseases. However, the underlying mechanisms by which PAD2 mediates host immunity remain largely unknown. In this review, we will discuss the role of PAD2 in different types of cell death signaling pathways and the related immune disorders contrasted with functions of PAD4, providing novel therapeutic strategies for PAD2-associated pathology.