Actions of Angiotensin II on Isolated Cardiac Fibroblasts

Abstract

Angiotensin (Ang) II contributes to myocardial hypertrophy by modulating fibroblast function. In the nonhypertrophied adult rat, rabbit, monkey and human heart, both angiotensin receptor subtypes, AT1 and AT2, are expressed. AT1 seems to be present on almost all myocardial cells, whereas AT2 has so far been localized to coronary endothelial cells and to fibroblasts. AT1 signaling in fibroblasts resembles in many aspects growth factor and cytokine signaling. It includes Ca2+ influx, protein kinase C activation, tyrosine phosphorylation of a number of proteins, activation of the JAK–STAT pathway, and protooncogene induction. Effects of Ang II on the cellular level include proliferation, migration, activation of paracrine–autocrine loops via TGF-β1 and other mediators, stimulation of cell–cell interaction, and synthesis of matrix proteins, i.e., collagens I and III and fibronectin. Ang II stimulation induces an increase in osteopontin, which then engages to the αvβ3 integrin receptor on the cell surface of the fibroblasts. These events appear necessary for increased DNA synthesis and collagen gel contractions. Several modulators of fibroblast function interfere with the effects of Ang II, including prostaglandins, which interact with matrix synthesis; nitric oxide, which modulates proliferation at the level of cell cycle regulation; and endothelin, which transmits Ang II-induced proliferation signals. Mechanical loading of intact hearts also affects isolated fibroblast function, and therefore, isolated fibroblasts from pressure- and volume-loaded animals exhibit specific features that interfere with matrix synthesis and calcium handling. Fibroblasts from explanted human hearts respond to Ang II and to Ang (1–7) by DNA and protein synthesis. So far, binding assays to identify angiotensin receptor subtypes have been inconclusive. PCR has consistently revealed the presence of AT1. It is possible that AT2 receptors are also present on human cardiac fibroblasts in vivo, but their number is downregulated by growth factors in cell culture. The question concerning the conditions under which Ang II stimulates collagen formation in human cardiac fibroblasts cannot yet be conclusively answered.