title: Exercise training attenuates age-dependent elevation of angiotensin II type 1 receptor and Nox2 signaling in the rat heart.
abstract: Fibrosis of the aging heart impedes cardiac function and increases the risk of arrhythmias and heart disease. Previously, we demonstrated that exercise-induced reduction of collagen I in the aging heart was linked to a suppression of oxidative stress and transforming growth factor-beta (TGF-ß). The renin-angiotensin II system (RAS) increases oxidative stress via NADPH oxidase-2 (Nox2) and thus elevates TGF-ß and collagen accumulation. Therefore, we tested the hypothesis that exercise training would alleviate age-related upregulation of the angiotensin II receptor I (AT1R) and NADPH oxidase-2 (Nox2), concomitant with suppression of TGF-β and fibrosis. Young (3 months, n=20) and old (31 months, n=20) Fischer 344 ×B rown Norway F1 (FBNF1) hybrid rats were assigned into sedentary and exercise groups, with exercise training rats training on a treadmill 45 min/day, 5 days/week for the next 12 weeks. Exercise training mitigated age-related upregulation of AT1R, Nox2 activity, and Nox2 subunits gp91phox and p47phox. Exercise training also attenuated TGF-ß positive staining and downstream effectors of fibrosis in the aging heart: connective tissue growth factor, phosphorylation of Smad2 at Ser423, myofibroblast proliferation, and collagen I-positive staining. Our results are consistent with the hypothesis that exercise training protects against age-dependent cardiac fibrosis by suppressing AT1R and Nox2 as part of a RAS-Nox2-TGF-β pathway.
authors.affiliation: Redox Biology and Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Redox Biology and Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, United States; Inha University, Department of Kinesiology, Republic of Korea.
authors.forename: Hyo-Bum
authors.initials: HB
authors.lastname: Kwak
authors.affiliation: Redox Biology and Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, United States.
authors.forename: Jeff
authors.initials: J
authors.lastname: Hord
authors.affiliation: Redox Biology and Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, United States; Hanyang University, Department of Physical Education, Republic of Korea.
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Redox Biology and Cell Signaling Laboratory, Department of Health and Kinesiology, Texas A&M University, United States. Electronic address: jml2621@email.tamu.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Lawler
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000379:methods*; D011916:Rats, Inbred F344; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D024042:Collagen Type I; D008562:Membrane Glycoproteins; D044140:Receptor, Angiotensin, Type 1; D053773:Transforming Growth Factor beta1; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: Aging; Angiotensin II receptor 1; Heart; NADPH oxidase; TGF-beta