Cardiac fibroblasts are the most prevalent cell type in the heart and play a key role
in regulating normal myocardial function and in the adverse myocardial remodeling
that occurs with hypertension, myocardial infarction and heart failure. Many of the
functional effects of cardiac fibroblasts are mediated through differentiation to
a myofibroblast phenotype that expresses contractile proteins and exhibits increased
migratory, proliferative and secretory properties. Cardiac myofibroblasts respond
to proinflammatory cytokines (e.g. TNFalpha, IL-1, IL-6, TGF-beta), vasoactive peptides
(e.g. angiotensin II, endothelin-1, natriuretic peptides) and hormones (e.g. noradrenaline),
the levels of which are increased in the remodeling heart. Their function is also
modulated by mechanical stretch and changes in oxygen availability (e.g. ischaemia-reperfusion).
Myofibroblast responses to such stimuli include changes in cell proliferation, cell
migration, extracellular matrix metabolism and secretion of various bioactive molecules
including cytokines, vasoactive peptides and growth factors. Several classes of commonly
prescribed therapeutic agents for cardiovascular disease also exert pleiotropic effects
on cardiac fibroblasts that may explain some of their beneficial outcomes on the remodeling
heart. These include drugs for reducing hypertension (ACE inhibitors, angiotensin
receptor blockers, beta-blockers), cholesterol levels (statins, fibrates) and insulin
resistance (thiazolidinediones). In this review, we provide insight into the properties
of cardiac fibroblasts that underscores their importance in the remodeling heart,
including their origin, electrophysiological properties, role in matrix metabolism,
functional responses to environmental stimuli and ability to secrete bioactive molecules.
We also review the evidence suggesting that certain cardiovascular drugs can reduce
myocardial remodeling specifically via modulatory effects on cardiac fibroblasts.