Remodelling of cardiac extracellular matrix during beta-adrenergic stimulation: upregulation of SPARC in the myocardium of adult rats.
Our objectives were (i) to evaluate the expression of several genes involved in the remodelling of cardiac extracellular matrix (ECM), with a special interest on SPARC (secreted protein acidic and rich in cysteine) a glycoprotein with anti-adhesive properties, and (ii) to characterise structural changes in the left (LV) and right (RV) ventricles of rats subjected to continuous beta-adrenergic stimulation. The rats were infused for 3 or 7 days with isoproterenol (ISO, 4 mg/kg/day) or vehicle. Hybridisation analysis was done for SPARC, atrial natriuretic peptide (ANP),alpha2 (I) [COL-I] and alpha1 (III) [COL-III] procollagens, TGF-beta1 and TGF-beta3 mRNA content. Interstitial and perivascular collagen deposition in both ventricles was measured after specific staining. The mean cross-sectional area of LV cardiomyocytes was evaluated by quantitative histomorphometry. ISO provoked an increase of LV mass, and a progressive enlargement of cardiomyocytes: their cross-sectional area raised from 205+/-8 micrometer2 in vehicle-treated animals to 247+/-4 and 296+/-9 micrometer2 after 3 or 7 days of ISO infusion, respectively (P<0.001). SPARC messenger abundance increased by more than 50% in LV and RV, a first evidence of its expression in the myocardium of adult rats. Transcripts of ANP, COL-III, TGF-beta1 and TGF-beta3 increased in both ventricles. COL-I transcript increased in LV (75 and 116% on days 3 and 7), but not in RV. In LV, collagen accumulated in the interstitium (2.69+/-0.20v 9. 23+/-0.50% of tissue area for vehicle and ISO 7 days groups, P<0.05) and around coronary arteries (1.04+/-0.11v 4.47+/-0.48% of lumen area for vehicle and ISO 7 days,P<0.05). Cardiac fibrosis was less marked in RV. In conclusion, early expression of SPARC, an anti-adhesive protein, and preferential expression of COL-III, a distensible form of collagen, should increase ECM plasticity and facilitate ventricular remodelling.
Masson
S
S
Centre for Biomedical and Pharmaceutical Research, Mario Negri Sud, Santa Maria Imbaro, Italy.
Arosio
B
B
Luvarà
G
G
Gagliano
N
N
Fiordaliso
F
F
Santambrogio
D
D
Vergani
C
C
Latini
R
R
Annoni
G
G
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000235:genetics; D006332:Cardiomegaly; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D015676:Osteonectin / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation
D000318:Adrenergic beta-Agonists; D015676:Osteonectin; D016212:Transforming Growth Factor beta; D009320:Atrial Natriuretic Factor; D003094:Collagen; D007545:Isoproterenol