Duchenne cardiomyopathy: targeting ROS and NOX4 as a promising therapeutic strategy

Figures & data

Table 1. NOX4 in cardiac disease models.

Disease model	NOX4 intervention (animal model)	Phenotypic outcome	Reference
Chronic stress (PO)	Global deletion (Nox4 KO mice)	Normal basal cardiac function. Contractile dysfunction, hypertrophy and cardiac dilatation.	Zhang et al. [6]
Chronic stress (PO)	Cardiomyocyte-specific overexpression (CM-Nox4 Tg mice)	Normal basal cardiac function. Reduced interstitial fibrosis and hypertrophy. Enhanced angiogenesis.	Zhang et al. [6]
Chronic stress (PO)	Cardiac-specific deletion (c-Nox4 KO mice)	Improved cardiac function. Decreased mitochondrial ROS production. Reduced hypertrophy, fibrosis, and cell death.	Kuroda et al. [9]
Chronic stress (PO)	Cardiac-specific overexpression (c-Nox4 Tg mice)	Exacerbated cardiac dysfunction. Increased fibrosis and cell death.	Kuroda et al. [9]
Chronic stress (PO)	Inducible cardiomyocyte-specific deletion (iCM-Nox4 KO mice)	Hypertrophy and contractile dysfunction. Increased interstitial fibrosis. Decreased angiogenesis.	Zhang et al. [7]
Chronic stress (PO)	Inducible endothelial-specific deletion (iEndo-Nox4 KO mice)	Hypertrophy and contractile dysfunction. Increased interstitial fibrosis. Decreased angiogenesis.	Zhang et al. [7]
Chronic disease (mdx)	No genetic modification of Nox4. Nox4 upregulation in mdx hearts	Cardiac dysfunction. Increased LV fibrosis.	Spurney et al. [11]
Chronic disease (mdx)	Global deletion (Nox4 KO mice)	Decreased LV fibrosis.	Hammers [12]
Chronic disease (DMD)	No genetic modification of NOX4. NOX4 upregulation in human iPSC-CMs	Increased cell death and mitochondrial ROS production.	Duelen et al. [13]
I/R injury	Global deletion (Nox4 KO mice)	Does not influence myocardial reperfusion injury	Braunersreuther et al. [14]
I/R injury	Global deletion (Nox4 KO mice)	Reduced myocardial damage and infarct size/area. Decreased ROS production.	Matsushima et al. [15]
I/R injury	Cardiac-specific deletion (c-Nox4 KO mice)	Reduced myocardial damage and infarct size/area. Decreased ROS production.	Matsushima et al. [15]

Abbreviations: c-Nox4: cardiac-specific Nox4; CM-Nox4: cardiomyocyte-specific Nox4; iCM: inducible 3 cardiomyocyte; iEndo: inducible endothelial; iPSC-CMs: induced pluripotent stem cell-derived cardiomyocytes; 4 I/R: ischemia/reperfusion; KO: knockout; LV: left ventricular; PO: pressure overload; Tg: transgenic.

Figure 1. Human induced pluripotent stem cells (hiPSCs) from Duchenne muscular dystrophy (DMD) patients were differentiated to cardiac myocytes to model dilated cardiomyopathy (DCM). Due to the absence of Dystrophin protein expression, cardiac myocytes are more vulnerable to contraction-induced ruptures of the cell membrane, leading to increased calcium (Ca²⁺) entry. Duelen and colleagues [13] demonstrated that hiPSC-derived cardiac myocytes (hiPSC-CMs) from patients with a genetic mutation in the DMD gene were subjected to significantly increased oxidative stress, partially as a result of increased expression and activity of ROS-producing NOX4 enzymes. Therefore, DMD hiPSC-CMs showed accelerated cell death. By administration of idebenone, beneficial effects were observed on the mitochondrial membrane potential, as well on the expression and the ROS-producing activity of NOX4, resulting in an increased cell survival and function of DMD iPSC-CMs. Abbreviations – DCM: dilated cardiomyopathy; DMD: Duchenne muscular dystrophy; hiPSCs: human induced pluripotent stem cells; NOX4: NADPH oxidase 4; ROS: reactive oxygen species. Created with BioRender.com.

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