Cardiac fibroblasts play a central role in the maintenance of extracellular matrix in the normal heart and as mediators of inflammatory and fibrotic myocardial remodeling in the injured and failing heart. In this review, we evaluate the cardiac fibroblast as a therapeutic target in heart disease. Unique features of cardiac fibroblast cell biology are discussed in relation to normal and pathophysiological cardiac function. The contribution of cardiac fibrosis as an independent risk factor in the outcome of heart failure is considered. Candidate drug therapies that derive benefit from actions on cardiac fibroblasts are summarized, including inhibitors of angiotensin-aldosterone systems, endothelin receptor antagonists, statins, anticytokine therapies, matrix metalloproteinase inhibitors, and novel antifibrotic/anti-inflammatory agents. These findings point the way to future challenges in cardiac fibroblast biology and pharmacotherapy.

The pro-inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) are elevated following acute myocardial infarction (MI) and have been implicated in the pathophysiology of cardiac disease progression. The cardiac fibroblast represents an important effector cell target for cytokine actions. In particular, cytokine-directed cardiac fibroblast migration is likely to impact both myocardial repair following acute MI and pathological myocardial remodeling in the progression to heart failure. In the present study, we examined the migratory response of neonatal rat cardiac fibroblasts to pro-inflammatory cytokines using modified Boyden chamber assays. On the basis of the knowledge of migration in other cell types, we hypothesized that members of the mitogen-activated protein kinase (MAPK) family may regulate this process. This possibility was addressed with the use of immunoblot detection of active phosphorylated MAPK species and pharmacological inhibitors for individual members of the MAPK cascades. IL-1beta stimulated robust and concentration-dependent increases in migration (maximum, 20-fold over control cells). TNF-alpha had lesser effect (fourfold increase over control). IL-6 did not induce migration. Activation of all three MAPK subfamilies (extracellular signal-regulated kinases, c-Jun NH(2)-terminal kinases, and p38) was shown to occur in response to cytokine stimulation. Fibroblast migration was attenuated by pharmacological inhibition of each MAPK subfamily. Understanding the regulation of cardiac fibroblast migration may provide insights in the search for therapies aimed at enhancing the functional nature of the remodeling process.

Active immunization of sheep against oxytocin prolonged the luteal phase of the oestrous cycle, as judged by oestrous behaviour and circulating progesterone concentrations. Mean cycle length was extended by 3.7 days. The treatment resulted in a 10-fold increase in circulating oxytocin concentrations. Antisera produced were specific for oxytocin; cross-reactions with vasotocin, arginine vasopressin, and hypothalamic releasing factors were low. Cerebrospinal fluid contained low levels of antibodies directed against oxytocin. This finding supports the hypothesis that the luteolytic action of oestradiol-17 beta in sheep may be mediated through a stimulatory effect on the endometrial oxytocin receptor concentration.

The secretion of prostaglandins (PGs) by bovine corpora lutea was investigated. Corpora lutea from the early, early-mid and late-mid stages of the luteal phase were dissociated by collagenase treatment and cultured in monolayer in Dulbecco's modified Eagle's medium containing 10% (v/v) fetal calf serum. Treatment with either LH (100 ng/ml) or dibutyryl cyclic AMP (dbcAMP; 1 mmol/l) had no effect on progesterone secretion by early luteal phase cells but stimulated progesterone secretion two-to fourfold by cells from the latter stages. The secretion rates, per \ g=m\ g cell protein, of 6-keto-PGF1\g=a\, PGE2 and PGF2\g=a\ were substantially greater in cells from the early luteal phase than in those from the latter stages, however, all changes in PG secretion in response to treatments were qualitatively similar between cells from the three stages of the luteal phase. The secretion rate of 6-keto\x=req-\ PGF1\g=a\ was greater than that of PGE2 or PGF2\g=a\ and was inhibited by treatment with indomethacin (28 \g=m\mol/l) but unaltered by treatment with LH, dbcAMP or butyrate (1 mmol/l). Secretion of PGE2 was inhibited by indomethacin but stimulated two\x=req-\ to threefold by treatment with either dbcAMP or butyrate. Secretion of PGF2\g=a\ was minimal and not inhibited further by treatment with indomethacin, but was stimulated 10-to 40-fold with dbcAMP. Indomethacin treatment inhibited the stimulatory effect of dbcAMP; butyrate had no effect on PGF2\g=a\ secretion. Treatment with LH had no effect on any of the PGs measured. In these experiments the secretion of progesterone appeared unrelated to any changes in the secretion of PGs. Thus it would appear that the production of progesterone by bovine luteal cells in culture is not related nor dependent upon the secretion of 6-keto-PGF1\g=a\, PGE2 or PGF2\g=a\, and that LH/cAMP does not regulate the secretion of PGs since LH had no effect on PG secretion and since the effects of dbcAMP appeared not to be through a cAMP-dependent pathway.