title: Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age.
abstract: Cardiovascular dysfunction is a primary independent predictor of age-related morbidity and mortality. Frailty is associated with activation of inflammatory pathways and fatigue that commonly presents and progresses with age. Interleukin 10 (IL-10), the cytokine synthesis inhibitory factor, is an anti-inflammatory cytokine produced by immune and non-immune cells. Homozygous deletion of IL-10 in mice yields a phenotype that is consistent with human frailty, including age-related increases in serum inflammatory mediators, muscular weakness, higher levels of IGF-1 at midlife, and early mortality. While emerging evidence suggests a role for IL-10 in vascular protection, a clear mechanism has not yet been elucidated.
  
  
  METHODS
  In order to evaluate the role of IL-10 in maintenance of vascular function, force tension myography was utilized to access ex-vivo endothelium dependent vasorelaxation in vessels isolated from IL-10 knockout IL-10(tm/tm) and control mice. Pulse wave velocity ((PWV), index of stiffness) of vasculature was measured using ultrasound and blood pressure was measured using the tail cuff method. Echocardiography was used to elucidated structure and functional changes in the heart.
  
  
  RESULTS
  Mean arterial pressures were significantly higher in IL-10(tm/tm) mice as compared to C57BL6/wild type (WT) controls. PWV was increased in IL-10(tm/tm) indicating stiffer vasculature. Endothelial intact aortic rings isolated from IL-10(tm/tm) mice demonstrated impaired vasodilation at low acetylcholine doses and vasoconstriction at higher doses whereas vasorelaxation responses were preserved in rings from WT mice. Cyclo-oxygenase (COX-2)/thromboxane A2 inhibitors improved endothelial dependent vasorelaxation and reversed vasoconstriction. Left ventricular end systolic diameter, left ventricular mass, isovolumic relaxation time, fractional shortening and ejection fraction were all significantly different in the aged IL-10(tm/tm) mice compared to WT mice.
  
  
  CONCLUSIONS
  Aged IL-10(tm/tm) mice have stiffer vessels and decreased vascular relaxation due to an increase in eicosanoids, specifically COX-2 activity and resultant thromboxane A2 receptor activation. Our results also suggest that aging IL-10(tm/tm) mice have an increased heart size and impaired cardiac function compared to age-matched WT mice. While further studies will be necessary to determine if this age-related phenotype develops as a result of inflammatory pathway activation or lack of IL-10, it is essential for maintaining the vascular compliance and endothelial function during the aging process. Given that a similar cardiovascular phenotype is present in frail, older adults, these findings further support the utility of the IL-10(tm/tm) mouse as a model of frailty.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA. gsikka1@johnshopkins.edu
authors.forename: Gautam
authors.initials: G
authors.lastname: Sikka
authors.forename: Karen L
authors.initials: KL
authors.lastname: Miller
authors.forename: Jochen
authors.initials: J
authors.lastname: Steppan
authors.forename: Deepesh
authors.initials: D
authors.lastname: Pandey
authors.forename: Sung M
authors.initials: SM
authors.lastname: Jung
authors.forename: Charles D
authors.initials: CD
authors.lastname: Fraser
authors.forename: Carla
authors.initials: C
authors.lastname: Ellis
authors.forename: Daniel
authors.initials: D
authors.lastname: Ross
authors.forename: Koenraad
authors.initials: K
authors.lastname: Vandegaer
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gabrielson
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Walston
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
authors.forename: Lili A
authors.initials: LA
authors.lastname: Barouch
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology; D062186:Arterial Pressure; D002318:Cardiovascular Diseases / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015150:Echocardiography, Doppler; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology; D005838:Genotype; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism*; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009213:Myography; D010641:Phenotype; D063177:Pulse Wave Analysis; D013318:Stroke Volume; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D059289:Vascular Stiffness; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C556062:IL10 protein, mouse; D018836:Inflammation Mediators; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D016753:Interleukin-10; D013928:Thromboxane A2; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2