Abstract
Metabolic syndrome (MetS), a complex of interrelated risk factors for cardiovascular disease and diabetes, is comprised of central obesity (increased waist circumference), hyperglycemia, dyslipidemia (high triglyceride blood levels, low high-density lipoprotein blood levels), and increased blood pressure. Oxidative stress, caused by the imbalance between pro-oxidant and endogenous antioxidant systems, is the primary pathological basis of MetS. The major sources of reactive oxygen species (ROS) associated with MetS are nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases and mitochondria. In this review, we summarize the current knowledge regarding the generation of ROS from NADPH oxidases and mitochondria, discuss the NADPH oxidase- and mitochondria-derived ROS signaling and pathophysiological effects, and the interplay between these two major sources of ROS, which leads to chronic inflammation, adipocyte proliferation, insulin resistance, and other metabolic abnormalities. The mechanisms linking MetS and chronic kidney disease are not well known. The role of NADPH oxidases and mitochondria in renal injury in the setting of MetS, particularly the influence of the pyruvate dehydrogenase complex in oxidative stress, inflammation, and subsequent renal injury, is highlighted. Understanding the molecular mechanism(s) underlying MetS may lead to novel therapeutic approaches by targeting the pyruvate dehydrogenase complex in MetS and prevent its sequelae of chronic cardiovascular and renal diseases.
Highlights
Metabolic syndrome (MetS), a complex of interrelated risk factors for cardiovascular disease and diabetes, is comprised of central obesity, hyperglycemia, dyslipidemia, and increased blood pressure (Alberti et al, 2009; Nilsson et al, 2019)
The presence of three of the five criteria qualifies a diagnosis of MetS: waist circumference ≥102 cm for males and ≥88 cm for females (≥90 cm and ≥80 cm for Asians, respectively); fasting blood glucose ≥5.6 mmol/L or drug treatment for elevated blood glucose; blood triglycerides ≥1.7 mmol/L or drug treatment for elevated blood triglycerides; reduced blood high-density lipoprotein cholesterol (
nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases in macrophages and other immune cells, adipocytes, endothelial cells, vascular smooth muscle cells (VSMCs), and renal epithelial cells play important roles in the initiation and progression of MetS by inducing inflammatory responses, adipogenesis and lipogenesis, insulin resistance, metabolic derangements, and increase in renal sodium transport and blood pressure
Summary
Metabolic syndrome (MetS), a complex of interrelated risk factors for cardiovascular disease and diabetes, is comprised of central obesity (increased waist circumference), hyperglycemia, dyslipidemia (high triglyceride blood levels, low high-density lipoprotein blood levels), and increased blood pressure (Alberti et al, 2009; Nilsson et al, 2019). Oxidative stress activates a series of stress pathways, modulates transcription factors, increases the generation of adipokines and cytokines, and causes derangements in metabolism, including impaired glucose tolerance, dyslipidemia, ectopic lipid accumulation, gut microbiota dysbiosis, and hypertension, leading to MetS (Rani et al, 2016; Vona et al, 2019). We discuss the generation of ROS from two major sources (NADPH oxidases and mitochondria), downstream signaling pathways, pathophysiological processes, and progression of MetS. ROS are generated by specific oxidase enzymes, such as the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidases, arachidonic acid monooxygenases, nitric oxide synthases, cyclooxygenases, cytochrome P450 enzymes, and lipoxygenases, as well as cell organelles, such as mitochondria, peroxisomes, and endoplasmic reticula (Zeng et al, 2009; Jia et al, 2016; Prasun, 2020). All NADPH oxidase members have two heme groups, six transmembrane domains, and flavin adenine dinucleotide (FAD) and NADPH binding sites
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