Role of ageing and coronary atherosclerosis in the development of cardiac fibrosis in the rabbit.
OBJECTIVE
Myocardial fibrosis contributes to the impairing of cardiac function and characterizes ageing, but is also a consequence of atherosclerotic ischemic disease. Since atherosclerosis is a slow progressive disease, which prevails in elderly populations, the aim of this study was to distinguish the contribution of ageing and atherosclerosis to cardiac fibrosis.


METHODS
Coronary atherosclerosis was induced in 5-6-year-old rabbits by a hyperlipemic diet for 9 months. Left ventricular (LV) collagen was quantified by densitometric analysis after Sirius-Red staining; an immunohistochemical investigation of the interstitium was also performed.


RESULTS
Atherosclerosis was associated to a marked increase of left ventricular interstitial collagen with the appearance of fibrotic foci and a decrease of coronary vessel endothelial nitric oxide synthase (eNOS) expression. In fibrotic foci, abundant macrophages co-localized with transforming growth factor beta-1 (TGFbeta-1)-positive myofibroblasts and vascular cell adhesion molecule-1 (VCAM-1) positive microvessels (52.3+/-3.9%). In normocholesterolemic rabbits, ageing resulted in a fourfold increase of myocardial interstitial collagen, with alpha-smooth muscle actin and TGFbeta-1 negative fibroblasts and VCAM-1 positive microvessels (19.4+/-1.2%) without macrophages, suggesting a role of endothelial dysfunction in age-related fibrosis.


CONCLUSIONS
There is a distinct difference between ageing and coronary atherosclerosis-induced cardiac fibrosis, although the effects may be cumulative. In the cascade of events leading to myocardial remodeling, reparative fibrosis with TGFbeta-1-positive myofibroblasts and interstitial inflammation were the major findings in atherosclerotic old rabbits, whereas with ageing alone, interstitial fibrosis with TGFbeta-1 negative fibroblasts and VCAM-1 positive microvessels prevailed.
Orlandi
Augusto
A
Department of Biopathology and Image Diagnostics, Anatomic Pathology Institute, Tor Vergata University of Rome, Via della Ricerca Scientifica, 00133 Rome, Italy. orlandi@uniroma2.it
Francesconi
Arianna
A
Marcellini
Marcella
M
Ferlosio
Amedeo
A
Spagnoli
Luigi Giusto
LG
D000199:Actins / Q000032:analysis / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D002452:Cell Count; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology*; D003331:Coronary Vessels / Q000473:pathology; D004730:Endothelium, Vascular / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011817:Rabbits; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism
D000199:Actins; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III