Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening
Chandrika Canugovi,
Mark D. Stevenson,
Aleksandr E. Vendrov,
Takayuki Hayami,
Jacques Robidoux,
Han Xiao,
You-Yi Zhang,
Daniel T. Eitzman,
Marschall S. Runge,
Nageswara R. Madamanchi
Affiliations
Chandrika Canugovi
1150 West Medical Center Drive, 7200 Medical Science Research Building III, Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA
Mark D. Stevenson
1150 West Medical Center Drive, 7200 Medical Science Research Building III, Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA
Aleksandr E. Vendrov
1150 West Medical Center Drive, 7200 Medical Science Research Building III, Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA
Takayuki Hayami
1150 West Medical Center Drive, 7200 Medical Science Research Building III, Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA
Jacques Robidoux
115 Heart Drive, Department of Pharmacology and Toxicology, The East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, 27834, North Carolina, USA
Han Xiao
Institute of Vascular Medicine, Cardiology Department, Peking University Third Hospital, NHC, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China
You-Yi Zhang
Institute of Vascular Medicine, Cardiology Department, Peking University Third Hospital, NHC, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China
Daniel T. Eitzman
1150 West Medical Center Drive, 7200 Medical Science Research Building III, Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA
Marschall S. Runge
1150 West Medical Center Drive, 7200 Medical Science Research Building III, Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA; Corresponding author.
Nageswara R. Madamanchi
1150 West Medical Center Drive, 7200 Medical Science Research Building III, Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA; Corresponding author.
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.
