title: Mitochondria DNA mutations cause sex-dependent development of hypertension and alterations in cardiovascular function.
abstract: Aging is associated with conduit artery stiffening that is a risk factor for and can precede hypertension and ventricular dysfunction. Increases in mitochondria DNA (mtDNA) frequency have been correlated with aging. Mice with a mutation in the encoding domain (D257A) of a proof-reading deficient version of mtDNA polymerase-γ (POLG) have musculoskeletal features of premature aging and a shortened lifespan. However, few studies using these mice have investigated the effects of mtDNA mutations on cardiovascular function. We hypothesized that the proof-reading deficient mtDNA POLG leads to arterial stiffening, hypertension, and ventricular hypertrophy. Ten to twelve month-old D257A mice (n=13) and age- and sex-matched wild-type controls (n=13) were catheterized for hemodynamic and ventricular function measurements. Left common carotid arteries (LCCA) were harvested for mechanical tests followed by histology. Male D257A mice had pulmonary and systemic hypertension, arterial stiffening, larger LCCA diameter (701±45 vs. 597±60μm), shorter LCCA axial length (8.96±0.56 vs. 10.10±0.80mm), and reduced hematocrit (29.1±6.1 vs. 41.3±8.1; all p<0.05). Male and female D257A mice had biventricular hypertrophy (p<0.05). Female D257A mice did not have significant increases in pressure or arterial stiffening, suggesting that the mechanisms of hypertension or arterial stiffening from mtDNA mutations differ based on sex. Our results lend insight into the mechanisms of age-related cardiovascular disease and may point to novel treatment strategies to address cardiovascular mortality in the elderly.
authors.affiliation: Department of Biomedical Engineering, UW-Madison College of Engineering, Madison, WI 53706, United States; Material Science Program, UW-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Golob
authors.affiliation: Department of Biomedical Engineering, UW-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: Lian
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Biomedical Engineering, UW-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, UW-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Zimmerman
authors.affiliation: Department of Biomedical Engineering, UW-Madison College of Engineering, Madison, WI 53706, United States.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Caneba
authors.affiliation: Department of Medicine, Medical Science Center, University of Wisconsin-Madison, Madison, WI 53706, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.affiliation: Department of Medicine, Medical Science Center, University of Wisconsin-Madison, Madison, WI 53706, United States.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Song
authors.affiliation: Department of Biomedical Engineering, UW-Madison College of Engineering, Madison, WI 53706, United States; Department of Medicine, Medical Science Center, University of Wisconsin-Madison, Madison, WI 53706, United States. Electronic address: chesler@engr.wisc.edu.
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Chesler
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001696:Biomechanical Phenomena; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology*; D002339:Carotid Arteries / Q000503:physiopathology; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006439:Hemodynamics; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009154:Mutation; D012727:Sex Characteristics; D016276:Ventricular Function
chemical_list: D004272:DNA, Mitochondrial
keywords: Elastic modulus; Hemodynamics; Hypertension; Mitochondria DNA; Ventricular function