angiotensinogen and Hyperplasia

Angiotensin II has been shown by many investigators to be a potent growth factor for vascular smooth cells in culture as well as in vivo. Depending on the conditions, the response of these cells is either hypertrophy or hyperplasia. These observations have important clinical implications, because it has been shown that angiotensin II participates in the hypertrophic response of the vessel wall during hypertension and the hyperplastic response after balloon angioplasty. Thus, an understanding of the molecular mechanism of these responses is important in the development of potential treatment strategies. This review examines the evidence for the growth-promoting properties of angiotensin II, concentrating on these molecular mechanisms. Hypotheses are presented that may explain the bifunctional effects (hypertrophy versus hyperplasia) of angiotensin II. These hypotheses revolve around the interaction of angiotensin with endothelium- and smooth muscle cell-derived products. These autocrine and paracrine interactions play important roles in the modulation of vascular structure.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Cell Division; Endothelium, Vascular; Humans; Hyperplasia; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; Renin-Angiotensin System

Increasing evidence suggests that angiotensin II (Ang II) may act as a growth factor for the heart. However, direct effects of Ang II on mammalian cardiac cells (myocytes and nonmyocytes), independent of secondary hemodynamic and neurohumoral effects, have not been well characterized. Therefore, we analyzed the molecular phenotype of cultured cardiac cells from neonatal rats in response to Ang II. In addition, we examined the effects of selective Ang II receptor subtype antagonists in mediating the biological effects of Ang II. In myocyte culture, Ang II caused an increase in protein synthesis without changing the rate of DNA synthesis. In contrast, Ang II induced increases in protein synthesis, DNA synthesis, and cell number in nonmyocyte cultures (mostly cardiac fibroblasts). The Ang II-induced hypertrophic response of myocytes and mitogenic response of fibroblasts were mediated primarily by the AT1 receptor. Ang II caused a rapid induction of many immediate-early genes (c-fos, c-jun, jun B, Egr-1, and c-myc) in myocyte and nonmyocyte cultures. Ang II induced "late" markers for cardiac hypertrophy, skeletal alpha-actin and atrial natriuretic factor expression, within 6 hours in myocytes. Ang II also caused upregulation of the angiotensinogen gene and transforming growth factor-beta 1 gene within 6 hours. Induction of immediate-early genes, late genes, and growth factor genes by Ang II was fully blocked by an AT1 receptor antagonist but not by an AT2 receptor antagonist. These results indicate that: (1) Ang II causes hypertrophy of cardiac myocytes and mitogenesis of cardiac fibroblasts, (2) the phenotypic changes of cardiac cells in response to Ang II in vitro closely mimic those of growth factor response in vitro and of load-induced hypertrophy in vivo, (3) all biological effects of Ang II examined here are mediated primarily by the AT1 receptor subtype, and (4) Ang II may initiate a positive-feedback regulation of cardiac hypertrophic response by inducing the angiotensinogen gene and transforming growth factor-beta 1 gene.

Topics: Angiotensin II; Angiotensinogen; Animals; Cardiomegaly; Cells, Cultured; Fibroblasts; Gene Expression Regulation; Genes, fos; Hyperplasia; Myocardium; Rats; Receptors, Angiotensin; Transforming Growth Factor beta