Chronic volume overload alters cardiac fibroblast secretion of collagen and matrix regulatory proteins

Abstract

Hearts with volume overload undergo progressive left ventricular dilatation with decreased extracellular matrix (ECM), associated with dynamic changes in bradykinin, angiotensin II, oxidative stress and the balance between pro‐ and anti‐fibrotic proteins. This study determined phenotypic changes in primary cultures of cardiac fibroblast (CF) isolated from rats subjected to aortocaval fistula (ACF) for 15 wk vs. aged‐matched shams. Western blot analysis and zymography measured basal and agonist induced expression of Ang II type 1 (AT1R) receptors, iNOS, and secretion of type I collagen, matrix metalloproteinases (MMPs) and plasminogen activator inhibitor‐1 (PAI‐1). ACF CFs demonstrated a 50% decrease in basal collagen type I and PAI‐1 expression and a 2‐3 fold increase in MMP‐9 and iNOS. Treatment with bradykinin (100 nM, 24hr) induced collagen secretion to a greater extent in CF from 15 wk sham vs. ACF. On the other hand, the NO‐donor DETA‐NONOate (100 μM 24 hr) increased MMP‐2/9 secretion by CF from 15 wk ACF to greater extent than CF from age‐matched shams. These data suggest that changes in CF function may underlie the persistent ECM degradation observed in vivo in chronic volume overload and may be associated with the transition to decompensated heart failure. Supported by R01HL063318 and P20RR18766 (PAL).