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    Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening

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    Author
    Canugovi, Chandrika; Stevenson, Mark D.; Vendrov, Aleksandr E.; Hayami, Takayuki; Robidoux, Jacques; Xiao, Han; Zhang, You-Yi; Eitzman, Daniel T.; Runge, Marschall S.; Madamanchi, Nageswara R.
    Abstract
    Aging is characterized by increased aortic stiffness, an early, independent predictor and cause of cardiovascular disease. Oxidative stress from excess reactive oxygen species (ROS) production increases with age. Mitochondria and NADPH oxidases (NOXs) are two major sources of ROS in cardiovascular system. We showed previously that increased mitochondrial ROS levels over a lifetime induce aortic stiffening in a mouse oxidative stress model. Also, NADPH oxidase 4 (NOX4) expression and ROS levels increase with age in aortas, aortic vascular smooth muscle cells (VSMCs) and mitochondria, and are correlated with age-associated aortic stiffness in hypercholesterolemic mice. The present study investigated whether young mice (4 months-old) with increased mitochondrial NOX4 levels recapitulate vascular aging and age-associated aortic stiffness. We generated transgenic mice with low (Nox4TG605; 2.1-fold higher) and high (Nox4TG618; 4.9-fold higher) mitochondrial NOX4 expression. Young Nox4TG618 mice showed significant increase in aortic stiffness and decrease in phenylephrine-induced aortic contraction, but not Nox4TG605 mice. Increased mitochondrial oxidative stress increased intrinsic VSMC stiffness, induced aortic extracellular matrix remodeling and fibrosis, a leftward shift in stress-strain curves, decreased volume compliance and focal adhesion turnover in Nox4TG618 mice. Nox4TG618 VSMCs phenocopied other features of vascular aging such as increased DNA damage, increased premature and replicative senescence and apoptosis, increased proinflammatory protein expression and decreased respiration. Aortic stiffening in young Nox4TG618 mice was significantly blunted with mitochondrial-targeted catalase overexpression. This demonstration of the role of mitochondrial oxidative stress in aortic stiffness will galvanize search for new mitochondrial-targeted therapeutics for treatment of age-associated vascular dysfunction.
    URI
    http://hdl.handle.net/10342/8091
    Date
    2019-08-02
    Citation:
    APA:
    Canugovi, Chandrika, & Stevenson, Mark D., & Vendrov, Aleksandr E., & Hayami, Takayuki, & Robidoux, Jacques, & Xiao, Han, & Zhang, You-Yi, & Eitzman, Daniel T., & Runge, Marschall S., & Madamanchi, Nageswara R.. (August 2019). Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening. Redox Biology, (1012882. Retrieved from http://hdl.handle.net/10342/8091

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    MLA:
    Canugovi, Chandrika, and Stevenson, Mark D., and Vendrov, Aleksandr E., and Hayami, Takayuki, and Robidoux, Jacques, and Xiao, Han, and Zhang, You-Yi, and Eitzman, Daniel T., and Runge, Marschall S., and Madamanchi, Nageswara R.. "Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening". Redox Biology. . (1012882.), August 2019. April 20, 2021. http://hdl.handle.net/10342/8091.
    Chicago:
    Canugovi, Chandrika and Stevenson, Mark D. and Vendrov, Aleksandr E. and Hayami, Takayuki and Robidoux, Jacques and Xiao, Han and Zhang, You-Yi and Eitzman, Daniel T. and Runge, Marschall S. and Madamanchi, Nageswara R., "Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening," Redox Biology 26, no. (August 2019), http://hdl.handle.net/10342/8091 (accessed April 20, 2021).
    AMA:
    Canugovi, Chandrika, Stevenson, Mark D., Vendrov, Aleksandr E., Hayami, Takayuki, Robidoux, Jacques, Xiao, Han, Zhang, You-Yi, Eitzman, Daniel T., Runge, Marschall S., Madamanchi, Nageswara R.. Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening. Redox Biology. August 2019; 26() 1012882. http://hdl.handle.net/10342/8091. Accessed April 20, 2021.
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