title: Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction.
abstract: Elevated interleukin-4 (IL-4) levels are associated with cardiac fibrosis in hypertension and heart failure in both patients and experimental animals. We hypothesized that chronically elevated IL-4 induces cardiac fibrosis, resulting in a predisposition of the heart to angiotensin II-induced damage. Wild-type Balb/c (WT, high circulating IL-4) and IL-4-deficient Balb/c mice (IL-4(-/-)) were used. WT mice exhibited cardiac fibrosis (evidenced by an increase in expression of procollagen genes/interstitial collagen fraction), enlarged left ventricle chamber, and declined cardiac function associated with a greater number of mast cells and macrophages in the heart compared with IL-4(-/-). In contrast, IL-4(-/-) mice had normal cardiac architecture/function while showing a 57.9% reduction in heart interstitial collagen compared with WT, despite elevated proinflammatory cytokines in heart tissue. In response to angiotensin II administration, IL-4(-/-) had reduced interstitial myocardial fibrosis and were protected from developing dilated cardiomyopathy, which was seen in WT mice. This was associated with increased macrophage infiltration into the hearts of WT mice, despite a similar degree of hypertension and increased cardiac transforming growth factor-β1 in both groups. In vitro data demonstrated that IL-4 upregulates procollagen genes and stimulates collagen production in mouse cardiac fibroblasts. This process is mediated by signal transducer and activator of transcription 6 signaling pathway via IL-4 receptor alpha. This study not only establishes a causal relationship between IL-4 and cardiac fibrosis/dysfunction, but also reveals a critical role for IL-4 in angiotensin II-induced cardiac damage. IL-4 could serve as an additional target for the treatment of cardiac fibrosis.
authors.affiliation: From the Hypertension and Vascular Research Division, Department of Internal Medicine (H.P., Z.S., X.-P.Y., J.X., B.J., N.R., O.A.C., N.-E.R.) and Department of Public Health Sciences (E.L.P.), Henry Ford Hospital, Detroit, MI. hpeng1@hfhs.org nrhaleb1@hfhs.org.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Peng
authors.affiliation: From the Hypertension and Vascular Research Division, Department of Internal Medicine (H.P., Z.S., X.-P.Y., J.X., B.J., N.R., O.A.C., N.-E.R.) and Department of Public Health Sciences (E.L.P.), Henry Ford Hospital, Detroit, MI.
authors.forename: Zeyd
authors.initials: Z
authors.lastname: Sarwar
authors.affiliation: From the Hypertension and Vascular Research Division, Department of Internal Medicine (H.P., Z.S., X.-P.Y., J.X., B.J., N.R., O.A.C., N.-E.R.) and Department of Public Health Sciences (E.L.P.), Henry Ford Hospital, Detroit, MI.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
authors.affiliation: From the Hypertension and Vascular Research Division, Department of Internal Medicine (H.P., Z.S., X.-P.Y., J.X., B.J., N.R., O.A.C., N.-E.R.) and Department of Public Health Sciences (E.L.P.), Henry Ford Hospital, Detroit, MI.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Peterson
authors.affiliation: From the Hypertension and Vascular Research Division, Department of Internal Medicine (H.P., Z.S., X.-P.Y., J.X., B.J., N.R., O.A.C., N.-E.R.) and Department of Public Health Sciences (E.L.P.), Henry Ford Hospital, Detroit, MI.
authors.forename: Jiang
authors.initials: J
authors.lastname: Xu
authors.affiliation: From the Hypertension and Vascular Research Division, Department of Internal Medicine (H.P., Z.S., X.-P.Y., J.X., B.J., N.R., O.A.C., N.-E.R.) and Department of Public Health Sciences (E.L.P.), Henry Ford Hospital, Detroit, MI.
authors.forename: Branislava
authors.initials: B
authors.lastname: Janic
authors.affiliation: From the Hypertension and Vascular Research Division, Department of Internal Medicine (H.P., Z.S., X.-P.Y., J.X., B.J., N.R., O.A.C., N.-E.R.) and Department of Public Health Sciences (E.L.P.), Henry Ford Hospital, Detroit, MI.
authors.forename: Nadia
authors.initials: N
authors.lastname: Rhaleb
authors.affiliation: From the Hypertension and Vascular Research Division, Department of Internal Medicine (H.P., Z.S., X.-P.Y., J.X., B.J., N.R., O.A.C., N.-E.R.) and Department of Public Health Sciences (E.L.P.), Henry Ford Hospital, Detroit, MI.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
authors.affiliation: From the Hypertension and Vascular Research Division, Department of Internal Medicine (H.P., Z.S., X.-P.Y., J.X., B.J., N.R., O.A.C., N.-E.R.) and Department of Public Health Sciences (E.L.P.), Henry Ford Hospital, Detroit, MI. hpeng1@hfhs.org nrhaleb1@hfhs.org.
authors.forename: Nour-Eddine
authors.initials: NE
authors.lastname: Rhaleb
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D000804:Angiotensin II; D015847:Interleukin-4
keywords: angiotensin II; balb/c mice; fibrosis; heart; interleukin-4