Hormonal regulation of cardiac fibroblast function

In arterial hypertension or congestive heart failure, myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). This reactive fibrosis presents as an excessive accumulation of fibrillar collagen within the normal connective tissue structures of the myocardium in either ventricle, irrespective of its haemodynamic load. It therefore would appear that circulating (hormonal) and not haemodynamic factors are responsible for this adverse fibrous tissue response. The cardiac fibroblast expresses mRNA for types I and III collagens, the major fibrillar collagens in the heart, and for collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Therefore, adult rat cardiac fibroblasts were cultured to ascertain whether the RAAS effector hormones angiotensin II (Ang II) or aldosterone (Aldo) directly stimulate collagen synthesis or inhibit MMP I production. Collagen synthesis, determined by 3 H-proline incorporation and MMP I activity determined by degradation of 14 C-collagen, were measured under serum-free conditions in confluent, quiescent fibroblasts after 24 h incubation with Ang II or Aldo over a wide range of concentrations (10 11 -10 -6 M). In addition, collagen synthesis was measured after incubation with the mineralocorticoid, deoxycorticosterone (DOC), or the prostaglandin, PGE 2 . Collagen synthesis, normalized per total protein synthesis, increased significantly in a dose-dependent manner after incubation with either mineralocorticoid hormone, Aldo or DOC, or after incubation with Ang II compared with untreated control cells. In contrast, collagen synthesis was significantly decreased with PGE 2 treatment. This increase in collagen synthesis in Ang II or mineralocorticoid-stimulated fibroblasts could be completely abolished by Ang II type I or mineralocorticoid receptor antagonists, respectively. In addition, Ang II significantly decreased MMP 1 activity, which appeared to be abolished by blockade ofAng II type 2 receptors, while PGE 2 significantly increased MMP I activity ; mineralocorticoid hormones had no effect on collagen degradation. Thus, either effector hormone of the RAA S, Ang II or Aldo, stimulate collagen synthesis in cultured adult rat cardiac fibroblasts via specific receptors, while PGE 2 , which would be elevated in myocardial tissue after angiotensin-converting enzyme inhibition, significantly inhibits it. In addition, and unlike mineralocorticoids, Ang II inhibits collagen degradation, while PGE 2 stimulates it. These findings suggest a direct interaction between Aldo, DOC, Ang II, PGE 2 and cardiac fibroblasts in regulating the collagen matrix in hypertensive heart disease or congestive heart failure, where circulating RAAS or tissue renin-angiotensin systems are activated.