Ca ²⁺ -Dependent NOX5 (NADPH Oxidase 5) Exaggerates Cardiac Hypertrophy Through Reactive Oxygen Species Production

Abstract

NOX5 (NADPH oxidase 5) is a homolog of the gp91 phox subunit of the phagocyte NOX, which generates reactive oxygen species. NOX5 is involved in sperm motility and vascular contraction and has been implicated in diabetic nephropathy, atherosclerosis, and stroke. The function of NOX5 in the cardiac hypertrophy is unknown. Because NOX5 is a Ca 2+ -sensitive, procontractile NOX isoform, we questioned whether it plays a role in cardiac hypertrophy. Studies were performed in (1) cardiac tissue from patients undergoing heart transplant for cardiomyopathy and heart failure, (2) NOX5-expressing rat cardiomyocytes, and (3) mice expressing human NOX5 in a cardiomyocyte-specific manner. Cardiac hypertrophy was induced in mice by transverse aorta coarctation and Ang II (angiotensin II) infusion. NOX5 expression was increased in human failing hearts. Rat cardiomyocytes infected with adenoviral vector encoding human NOX5 cDNA exhibited elevated reactive oxygen species levels with significant enlargement and associated increased expression of ANP (atrial natriuretic peptides) and β-MHC (β-myosin heavy chain) and prohypertrophic genes ( Nppa , Nppb , and Myh7 ) under Ang II stimulation. These effects were reduced by N-acetylcysteine and diltiazem. Pressure overload and Ang II infusion induced left ventricular hypertrophy, interstitial fibrosis, and contractile dysfunction, responses that were exaggerated in cardiac-specific NOX5 trangenic mice. These phenomena were associated with increased reactive oxygen species levels and activation of redox-sensitive MAPK (mitogen-activated protein kinase). N-acetylcysteine treatment reduced cardiac oxidative stress and attenuated cardiac hypertrophy in NOX5 trangenic. Our study defines Ca 2+ -regulated NOX5 as an important NOX isoform involved in oxidative stress- and MAPK-mediated cardiac hypertrophy and contractile dysfunction.

Influence of cardiometabolic comorbidities on myocardial function, infarction, and cardioprotection: Role of cardiac redox signaling

“…Widespread disturbance of cellular redox balance throughout the circulatory system is recognized as a general feature of arterial hypertension, whether of primary or secondary etiology. In experimental models of hypertension or other forms of pressure overload, LVH is accompanied by many biochemical, metabolic and signaling disturbances that have been associated with cardiomyocyte hypertrophy, altered myofibrillar contractility, interstitial fibrosis and gradual progression to Calcium/calmodulin-dependent NOX5 may also be implicated [283]. The extent to which these various pathways of ROS production are co-regulated or exhibit cross-talk is unclear.…”

Aerobic Exercise During Advance Stage of Uncontrolled Arterial Hypertension

“…The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex is an important source of ROS in the heart ( Touyz et al, 2020 ). Increased NADPH oxidase activity and expression has been associated with LV hypertrophy in pressure overload models ( Li et al, 2002 ; Zhao et al, 2020 ). The main cellular defenses against increased ROS include enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) ( D’Oria et al, 2020 ).…”

Expression of Endothelial NOX5 Alters the Integrity of the Blood-Brain Barrier and Causes Loss of Memory in Aging Mice

“…For instance, NOX5-dependent ROS increased the systolic blood pressure levels in a podocyte-specific NOX5 expression knock-in mouse model [ 35 ] or participated in diabetic nephropathy progression [ 36 ]. Moreover, NOX5 is known to potentiate cardiac remodeling and the dysfunction of hypertensive angiotensin II-induced mice expressing NOX5 in the heart under the α-myosin heavy-chain promoter [ 37 ]. Additionally, in another knock-in mouse, which expressed NOX5 under the Tie2 promoter specific to the endothelium and white blood cells, the authors found that chronic NOX5 expression induced elevated systolic blood pressure levels in aging mice [ 38 ].…”