title: The α11 integrin mediates fibroblast-extracellular matrix-cardiomyocyte interactions in health and disease.
abstract: Excessive cardiac interstitial fibrosis impairs normal cardiac function. We have shown that the α11β1 (α11) integrin mediates fibrotic responses to glycated collagen in rat myocardium by a pathway involving transforming growth factor-β. Little is known of the role of the α11 integrin in the developing mammalian heart. Therefore, we examined the impact of deletion of the α11 integrin in wild-type mice and in mice treated with streptozotocin (STZ) to elucidate the role of the α11 integrin in normal cardiac homeostasis and in the pathogenesis of diabetes-related fibrosis. As anticipated, cardiac fibrosis was reduced in α11 integrin knockout mice (α11(-/-); C57BL/6 background) treated with STZ compared with STZ-treated wild-type mice (P < 0.05). Unexpectedly, diastolic function was impaired in both vehicle and STZ-treated α11(-/-) mice, as shown by the decreased minimum rate of pressure change and prolonged time constant of relaxation in association with increased end-diastolic pressure (all P < 0.05 compared with wild-type mice). Accordingly, we examined the phenotype of untreated α11(-/-) mice, which demonstrated a reduced cardiomyocyte cross-sectional cell area and myofibril thickness (all P < 0.05 compared with wild-type mice) and impaired myofibril arrangement. Immunostaining for desmin and connexin 43 showed abnormal intermediate filament organization at intercalated disks and impaired gap-junction development. Overall, deletion of the α11 integrin attenuates cardiac fibrosis in the mammalian mouse heart and reduces ECM formation as a result of diabetes. Furthermore, α11 integrin deletion impairs cardiac function and alters cardiomyocyte morphology. These findings shed further light on the poorly understood interaction between the fibroblast-cardiomyocyte and the ECM.
authors.affiliation: Keenan Research Center for Biomedical Science, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Civitarese
authors.affiliation: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Ilana
authors.initials: I
authors.lastname: Talior-Volodarsky
authors.affiliation: Keenan Research Center for Biomedical Science, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada;
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Desjardins
authors.affiliation: Keenan Research Center for Biomedical Science, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada;
authors.forename: Golam
authors.initials: G
authors.lastname: Kabir
authors.affiliation: Keenan Research Center for Biomedical Science, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Switzer
authors.affiliation: Keenan Research Center for Biomedical Science, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada;
authors.forename: Melissa
authors.initials: M
authors.lastname: Mitchell
authors.affiliation: Keenan Research Center for Biomedical Science, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada;
authors.forename: Andras
authors.initials: A
authors.lastname: Kapus
authors.affiliation: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: McCulloch
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Donald
authors.initials: D
authors.lastname: Gullberg
authors.affiliation: Keenan Research Center for Biomedical Science, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada; connellyk@smh.ca.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
mesh_terms: D000818:Animals; D048429:Cell Size; D018031:Connexin 43 / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005838:Genotype; D039001:Integrin alpha Chains / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009210:Myofibrils / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction; D013311:Streptozocin; D013318:Stroke Volume; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
chemical_list: D018031:Connexin 43; D003893:Desmin; C543076:GJA1 protein, mouse; D039001:Integrin alpha Chains; C000610207:integrin alpha11, mouse; D013311:Streptozocin
keywords: ECM; cardiac development/function; diabetes; fibrosis; integrins