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Increased adrenergic drive and Angiotensin II promote an anti‐fibrotic phenotype in dog cardiac fibroblasts
Author(s) -
Pat Betty,
Killingsworth Cheryl,
Dillon Ray,
Dell’Italia Louis J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1429-a
Subject(s) - fibronectin , angiotensin ii , medicine , extracellular matrix , endocrinology , chemistry , matrix metalloproteinase , myofibroblast , cardiac fibrosis , renin–angiotensin system , fibrosis , volume overload , heart failure , blood pressure , biochemistry
We have shown that volume overload (VO) in the canine model of mitral regurgitation (MR) is characterized by LV dilatation and loss of extracellular matrix (ECM), in the presence of increased angiotensin II (Ang II) and catecholamines in the interstitial fluid (ISF). Ang II usually promotes matrix production. In VO, we hypothesize that Ang II and catecholamines decrease fibroblast activation and increase matrix degradation. Cardiac fibroblasts (CFs) isolated from the LV of normal adult dogs were treated with Ang II (100 nM), isoproterenol (ISO, 100 nM) or both agents for 24 hrs then analyzed for myofibroblast activation by α‐smooth muscle actin (α‐SMA), ECM synthesis, and matrix metalloproteinase‐2 (MMP‐2) activity. Ang II produced an increase in α‐SMA and fibronectin (FN) production. There was a trend towards decreased α‐SMA and FN after ISO treatment. However, Ang II + ISO caused a significant decrease in α‐SMA and FN expression (18% and 24% respectively). In addition, Ang II + ISO produced an increase in MMP‐2 activity that was not found with Ang II or ISO alone. Thus, the synergistic effect of Ang II and increased catecholamines in the cardiac ISF of the volume overloaded heart blunt ECM production and promote MMP activation. This may explain why renin‐angiotensin system blockade, which blocks ECM production, is ineffective in attenuating the LV dilatation in the pure volume overload of MR in the dog and the human.