title: Differential patterns of replacement and reactive fibrosis in pressure and volume overload are related to the propensity for ischaemia and involve resistin.
abstract: Pathological left ventricle (LV) hypertrophy (LVH) results in reactive and replacement fibrosis. Volume overload LVH (VOH) is less profibrotic than pressure overload LVH (POH). Studies attribute subendocardial fibrosis in POH to ischaemia, and reduced fibrosis in VOH to collagen degradation favouring dilatation. However, the mechanical origin of the relative lack of fibrosis in VOH is incompletely understood. We hypothesized that reduced ischaemia propensity in VOH compared to POH accounted for the reduced replacement fibrosis, along with reduced reactive fibrosis. Rats with POH (ascending aortic banding) evolved into either compensated-concentric POH (POH-CLVH) or dilated cardiomyopathy (POH-DCM); they were compared to VOH (aorta-caval fistula). We quantified LV fibrosis, structural and haemodynamic factors of ischaemia propensity, and the activation of profibrotic pathways. Fibrosis in POH-DCM was severe, subendocardial and subepicardial, in contrast with subendocardial fibrosis in POH-CLVH and nearly no fibrosis in VOH. The propensity for ischaemia was more important in POH versus VOH, explaining different patterns of replacement fibrosis. LV collagen synthesis and maturation, and matrix metalloproteinase-2 expression, were more important in POH. The angiotensin II-transforming growth-factor β axis was enhanced in POH, and connective tissue growth factor (CTGF) was overexpressed in all types of LVH. LV resistin expression was markedly elevated in POH, mildly elevated in VOH and independently reflected chronic ischaemic injury after myocardial infarction. In vitro, resistin is induced by angiotensin II and induces CTGF in cardiomyocytes. Based on these findings, we conclude that a reduced ischaemia propensity and attenuated upstream reactive fibrotic pathways account for the attenuated fibrosis in VOH versus POH.
authors.affiliation: D. Lebeche: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA. djamel.lebeche@mssm.edu.
authors.forename: Elie R
authors.initials: ER
authors.lastname: Chemaly
authors.forename: Soojeong
authors.initials: S
authors.lastname: Kang
authors.forename: Shihong
authors.initials: S
authors.lastname: Zhang
authors.forename: LaTronya
authors.initials: L
authors.lastname: McCollum
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Chen
authors.forename: Ludovic
authors.initials: L
authors.lastname: Bénard
authors.forename: K-Raman
authors.initials: KR
authors.lastname: Purushothaman
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D052243:Resistin / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: C526316:CCN2 protein, rat; D052243:Resistin; C499622:Retn protein, rat; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D003094:Collagen; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
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