An adverse structural remodeling of the myocardium by fibrous tissue has been linked to abnormal tissue stiffness and could therefore contribute to organ failure. Myocardial fibrosis has been associated with the mineralocorticoid (MC) hormones aldosterone (ALDO) and deoxycorticosterone. Administration of ALDO to rats produces perivascular fibrosis which can be blocked by the ALDO antagonist spironalactone. ALDO action is via type 1 MC receptors (MR), which possess equal affinity for ALDO and more plentiful glucocorticoids (GC). In vivo specificity of MR is conferred by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) which metabolizes GC to 11-ketosteroids. Two distinct isoforms of 11 beta-HSD have been described (11 beta-HSD1 and 11 beta-HSD2) and we have shown that both are active in human heart. We hypothesize that both isoforms play a role in modulating MC/GC effects on cardiac structure. Vascular endothelial cells elaborate ALDO and corticosterone as well as progesterone and progesterone metabolites, which exert a considera ble inhibitory effect on both isoforms of 11 beta-HSD. We hypothesize that endothelial-derived progesterone and its metabolites function in a paracrine fashion, to regulate 11 beta-HSD activity in neighboring cells. To test these hypotheses we propose to utilize cell culture and in vivo techniques, including well-established ALDO infusion models and a skin pouch model of wound healing which permits the generation of large quantities of granulation tissue without the effects of confounding hemodynamic factors.
The specific aims are as follows:
Specific Aim number 1: to study corticosteroid/11 beta-HSD- mediated effects on Ang II action and collagen synthesis in cultured cardiac fibroblasts.
Specific Aim number 2: to investigate AngII/ corticosteroid-mediated cardiac fibrosis in a rat model.
Specific Aim number 3: to study (A) corticosteroid-mediated mechanisms of fibrous tissue formation in a rat skin pouch and (B) measure MC/GC elaboration by skin pouch.
Specific Aim number 4: to (A) measure endothelias- derived progesterone and progesterone metabolites and (B) study their paracrine modulation of fibroblast 11 beta-HSD activity and collagen turnover using co-culture methodology.
| Lamparter, Steffen; Slight, Simon H; Weber, Karl T (2002) Doxycycline and tissue repair in rats. J Lab Clin Med 139:295-302 |
| Slight, S H; Joseph, J; Ganjam, V K et al. (1999) Extra-adrenal mineralocorticoids and cardiovascular tissue. J Mol Cell Cardiol 31:1175-84 |
