title: MCIP1 overexpression suppresses left ventricular remodeling and sustains cardiac function after myocardial infarction.
abstract: Pathological remodeling of the left ventricle (LV) after myocardial infarction (MI) is a major cause of heart failure. Although cardiac hypertrophy after increased loading conditions has been recognized as a clinical risk factor for human heart failure, it is unknown whether post-MI hypertrophic remodeling of the myocardium is beneficial for cardiac function over time, nor which regulatory pathways play a crucial role in this process. To address these questions, transgenic (TG) mice engineered to overexpress modulatory calcineurin-interacting protein-1 (MCIP1) in the myocardium were used to achieve cardiac-specific inhibition of calcineurin activation. MCIP1-TG mice and their wild-type (WT) littermates, were subjected to MI and analyzed 4 weeks later. At 4 weeks after MI, calcineurin was activated in the LV of WT mice, which was significantly reduced in MCIP1-TG mice. WT mice displayed a 78% increase in LV mass after MI, which was reduced by 38% in MCIP1-TG mice. Echocardiography indicated marked LV dilation and loss of systolic function in WT-MI mice, whereas TG-MI mice displayed a remarkable preservation of LV geometry and contractility, a pronounced reduction in myofiber hypertrophy, collagen deposition, and beta-MHC expression compared with WT-MI mice. Together, these results reveal a protective role for MCIP1 in the post-MI heart and suggest that calcineurin is a crucial regulator of postinfarction-induced pathological LV remodeling. The improvement in functional, structural, and molecular abnormalities in MCIP1-TG mice challenges the adaptive value of post-MI hypertrophy of the remote myocardium. The full text of this article is available online at http://circres.ahajournals.org.
authors.affiliation: Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands. dewindt@niob.knaw.nl
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Harry J G M
authors.initials: HJ
authors.lastname: Crijns
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heeneman
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lips
authors.forename: Marc
authors.initials: M
authors.lastname: van Bilsen
authors.forename: R Sanders
authors.initials: RS
authors.lastname: Williams
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D015152:Blotting, Northern; D019703:Calcineurin / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004268:DNA-Binding Proteins; D004452:Echocardiography; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology*; D018995:Myosin Heavy Chains / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D003094:Collagen; D019703:Calcineurin; D018995:Myosin Heavy Chains