Nox4TG618 transgenic mice have increased expression of mitochondrial NOX4 driven by a CAG promoter. Mice from this founder line 618 have one copy of the transgene which results in 4.9-fold higher NOX4 expression specifically in mitochondria, and a 20-fold increase in Nox4 mRNA. Nox4 encodes NADPH oxidase 4, the catalytic subunit the NADPH oxidase complex. It acts as an oxygen sensor and catalyzes the reduction of molecular oxygen to various reactive oxygen species (ROS). The ROS generated by this protein have been implicated in oxidative stress in signal transduction, cell differentiation and tumor cell growth. Oxidative stress and mitochondrial dysfunction from excess reactive oxygen species (ROS) production increases with age and atherosclerotic lesion severity. Mitochondria are a major source of ROS production in cardio system and mitochondrial oxidative stress contributions to diastolic dysfunction which underlies heart failure associated with aging. Four-month-old Nox4TG618 transgenic mice have a 146% increase in aortic hydrogen peroxide (H2O2) levels and a 76% increase in mitochondrial H2O2 production compared to wildtype mice. Mice display increased mitochondrial oxidative stress and dysfunction, and a cardiovascular phenotype which includes aortic stiffness, diastolic dysfunction, and atrial and ventricular arrhythmias. In these mice, mitochondrial oxidative stress contributes to diastolic dysfunction by causing mitochondrial dysfunction, impaired mitochondrial dynamics, increased synthesis of pro-inflammatory and pro-fibrotic cytokines, activation of fibroblasts, and the accumulation of extracellular matrix, which leads to interstitial fibrosis and passive stiffness of the myocardium. Hemizygous mice and homozygous mice are viable and fertile and are not immunodeficient. They do not show any gross phenotypic abnormalities in weight, behavior, fertility, or longevity.

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Nox4TG618 transgenic mice have 4.9-fold higher mitochondrial expression of NOX4, making them useful when studying mitochondrial oxidative stress in aortic stiffness and age-associated vascular dysfunction.

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