title: Low intrinsic exercise capacity in rats predisposes to age-dependent cardiac remodeling independent of macrovascular function.
abstract: Rats selectively bred for low (LCR) or high (HCR) intrinsic running capacity simultaneously present with contrasting risk factors for cardiovascular and metabolic disease. However, the impact of these phenotypes on left ventricular (LV) morphology and microvascular function, and their progression with aging, remains unresolved. We tested the hypothesis that the LCR phenotype induces progressive age-dependent LV remodeling and impairments in microvascular function, glucose utilization, and β-adrenergic responsiveness, compared with HCR. Hearts and vessels isolated from female LCR (n = 22) or HCR (n = 26) were studied at 12 and 35 wk. Nonselected N:NIH founder rats (11 wk) were also investigated (n = 12). LCR had impaired glucose tolerance and elevated plasma insulin (but not glucose) and body-mass at 12 wk compared with HCR, with early LV remodeling. By 35 wk, LV prohypertrophic and glucose transporter GLUT4 gene expression were up- and downregulated, respectively. No differences in LV β-adrenoceptor expression or cAMP content between phenotypes were observed. Macrovascular endothelial function was predominantly nitric oxide (NO)-mediated in both phenotypes and remained intact in LCR for both age-groups. In contrast, mesenteric arteries microvascular endothelial function, which was impaired in LCR rats regardless of age. At 35 wk, endothelial-derived hyperpolarizing factor-mediated relaxation was impaired whereas the NO contribution to relaxation is intact. Furthermore, there was reduced β2-adrenoceptor responsiveness in both aorta and mesenteric LCR arteries. In conclusion, diminished intrinsic exercise capacity impairs systemic glucose tolerance and is accompanied by progressive development of LV remodeling. Impaired microvascular perfusion is a likely contributing factor to the cardiac phenotype.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Ritchie
authors.forename: Chen Huei
authors.initials: CH
authors.lastname: Leo
authors.forename: Chengxue
authors.initials: C
authors.lastname: Qin
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Stephenson
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Bowden
authors.forename: Keith D
authors.initials: KD
authors.lastname: Buxton
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lessard
authors.forename: Donato A
authors.initials: DA
authors.lastname: Rivas
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Koch
authors.forename: Steven L
authors.initials: SL
authors.lastname: Britton
authors.forename: John A
authors.initials: JA
authors.lastname: Hawley
authors.forename: Owen L
authors.initials: OL
authors.lastname: Woodman
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001685:Biological Factors / Q000378:metabolism; D003326:Coronary Circulation / Q000502:physiology*; D017079:Exercise Tolerance / Q000235:genetics / Q000502:physiology*; D005260:Female; D005355:Fibrosis / Q000503:physiopathology; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D024821:Metabolic Syndrome / Q000235:genetics / Q000503:physiopathology; D008833:Microcirculation / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014655:Vascular Resistance / Q000502:physiology; D014664:Vasodilation / Q000502:physiology; D024723:Ventricular Myosins / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D001685:Biological Factors; D051275:Glucose Transporter Type 4; D011943:Receptors, Adrenergic, beta; C495694:Slc2a4 protein, rat; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D024723:Ventricular Myosins