NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets

Abstract

Reactive oxygen species (ROS)-dependent production of ROS underlies sustained oxidative stress, which has been implicated in the pathogenesis of cardiovascular diseases such as hypertension, aortic aneurysm, hypercholesterolaemia, atherosclerosis, diabetic vascular complications, cardiac ischaemia-reperfusion injury, myocardial infarction, heart failure and cardiac arrhythmias. Interactions between different oxidases or oxidase systems have been intensively investigated for their roles in inducing sustained oxidative stress. In this Review, we discuss the latest data on the pathobiology of each oxidase component, the complex crosstalk between different oxidase components and the consequences of this crosstalk in mediating cardiovascular disease processes, focusing on the central role of particular NADPH oxidase (NOX) isoforms that are activated in specific cardiovascular diseases. An improved understanding of these mechanisms might facilitate the development of novel therapeutic agents targeting these oxidase systems and their interactions, which could be effective in the prevention and treatment of cardiovascular disorders.

Fig. 1 |. NADPH oxidase-dependent oxidase crosstalk in the pathogenesis of cardiovascular diseases.

NADPH oxidase (NOX)-derived reactive oxygen species (ROS) production induces endothelial nitric oxide synthase (eNOS) uncoupling and mitochondrial dysfunction, resulting in sustained oxidative stress and the development of cardiovascular diseases. Reference numbers are given in square brackets. AAA, abdominal aortic aneurysm; AKT, RACα serine/threonine-protein kinase; ANGII, angiotensin II; BBB, blood–brain barrier; BMP4, bone morphogenetic protein 4; BRG1, transcription activator BRG1; DHFR, dihydrofolate reductase; DOCA, deoxycorticosterone acetate; GTPCH1, GTP cyclohydrolase 1; H₂O₂, hydrogen peroxide; H₄B, tetrahydrobiopterin; HDAC4, histone deacetylase 4; HIF1α, hypoxia-inducible factor 1α; IR, ischaemia–reperfusion; LTCC, L-type calcium channel; MAPK, mitogen-activated protein kinase; Mito, mitochondrial; Mito-ROS, mitochondria-derived reactive oxygen species; mTOR, mechanistic target of rapamycin; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor-κB; N if, nifedipine; NO, nitric oxide; PE, phenylephrine; PO, pressure overload; PPARα, peroxisome proliferator-activated receptor-α; SPR, sepiapterin reductase; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; VEGF, vascular endothelial growth factor.

Fig. 2 |. Composition and cell-specific expression and activity of NOX isoforms in the cardiovascular system.

a | NADPH oxidase 1 (NOX1). b | NOX2. c | NOX4. d | NOX5. e | Dual oxidase 1 (DUOX1). f | DUOX2. CaM, calmodulin; DUOXA, dual oxidase maturation factor; HSP90, heat shock protein 90; NOXA1, NADPH oxidase activator 1; NOXO1, NADPH oxidase organizer 1; POLDIP2, polymerase δ-interacting protein 2.