Abstract
Renal and lung fibrosis was characterized by the accumulation of collagen-immunoreactive mesenchymal cells expressing the intermediate filament protein nestin. The present study tested the hypothesis that nestin expression was increased in the hypertrophied/fibrotic left ventricle of suprarenal abdominal aorta constricted adult male Sprague-Dawley rats and induced in ventricular fibroblasts by pro-fibrotic peptide growth factors. Nestin protein levels were upregulated in the pressure-overloaded left ventricle and expression positively correlated with the rise of mean arterial pressure. In sham and pressure-overloaded hearts, nestin immunoreactivity was detected in collagen type I(+)-and CD31(+)-cells identified in the interstitium and perivascular region whereas staining was absent in smooth muscle α-actin(+)-cells. A significantly greater number of collagen type I(+)-cells co-expressing nestin was identified in the left ventricle of pressure-overloaded rats. Moreover, an accumulation of nestin(+)-cells lacking collagen, CD31 and smooth muscle α-actin staining was selectively observed at the adventitial region of predominantly large calibre blood vessels in the hypertrophied/fibrotic left ventricle. Angiotensin II and TGF-β1 stimulation of ventricular fibroblasts increased nestin protein levels via phosphatidylinositol 3-kinase- and protein kinase C/SMAD3-dependent pathways, respectively. CD31/eNOS(+)-rat cardiac microvascular endothelial cells synthesized/secreted collagen type I, expressed prolyl 4-hydroxylase and TGF-β1 induced nestin expression. The selective accumulation of adventitial nestin(+)-cells highlighted a novel feature of large vessel remodelling in the pressure-overloaded heart and increased appearance of collagen type I/nestin(+)-cells may reflect an activated phenotype of ventricular fibroblasts. CD31/collagen/nestin(+)-interstitial cells could represent displaced endothelial cells displaying an unmasked mesenchymal phenotype, albeit contribution to the reactive fibrotic response of the pressure-overloaded heart remains unknown.
Highlights
Reactive fibrosis characterized by the uncontrolled synthesis and deposition of extracellular matrix proteins by ventricular fibroblasts represents a secondary pathological consequence of concentric cardiac hypertrophy.[1]
Work from our lab and others have reported the selective appearance of a modest population of nestin(+)-cardiomyocytes at the peri-infarct/infarct region following ischemic damage. [23,24] In the present study, a paucity of nestin(+)-cardiomyocytes was detected in the hypertrophied heart after suprarenal abdominal aorta constriction of adult male Sprague-Dawley rats
Concentric remodeling of the heart was associated with ischemic injury and may represent the incipient event promoting in part the subsequent reactive fibrotic response.[25]
Summary
Reactive fibrosis characterized by the uncontrolled synthesis and deposition of extracellular matrix proteins by ventricular fibroblasts represents a secondary pathological consequence of concentric cardiac hypertrophy.[1]. Several distinct functions were attributed to nestin including cellular proliferation, migration and a pro-survival anti-apoptotic phenotype.[6,7,14,15,16,17] Collectively, these observations provided the impetus to test the hypothesis that nestin protein levels were upregulated in the hypertrophied/fibrotic left ventricle following suprarenal abdominal aorta constriction of adult male Sprague-Dawley rats and induction of the intermediate filament protein in ventricular fibroblasts by putative pro-fibrotic peptide growth factors may represent a phenotypic marker of an activated state during reactive fibrosis
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