The regulation of the inflammatory response through nuclear factor-kappab pathway by angiotensin IV extends the role of the renin angiotensin system in cardiovascular diseases

Abstract

The renin angiotensin system (RAS) participates in the pathogenesis of cardiovascular diseases. Although angiotensin II has been considered the effector peptide of RAS, accumulating evidence shows that other RAS peptides also posses important functions, some of them involved in cardiovascular pathology. Many studies support the importance of N-terminal angiotensin degradation product, angiotensin IV (AngIV), in the fields of cognition, renal metabolism, and pathophysiologic conditions. The novel data discussed here show that AngIV could contribute to cardiovascular damage. Angiotensin IV can be generated by degradation of angiotensin II, by aminopeptidase (AP) N, or by other proteases, which could be activated during tissue damage, suggesting that elevated AngIV levels can be found in pathologic conditions. Angiotensin IV binds to a specific receptor, AT(4), which has recently been identified as an insulin-regulated AP. In vascular cells, correspondence between AT(4) binding sites and insulin-regulated AP has been described. Angiotensin IV regulates cell growth in cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells (VSMCs). In VSMC, AngIV, through AT(4), independently of AT(1) and AT(2) receptors, activates the nuclear factor-kappaB pathway and up-regulates several nuclear factor-kappaB-related genes, including the monocyte chemokine monocyte chemoattractant protein-1, the adhesion molecule intercellular adhesion molecule-1, and the cytokines interleukin 6 and tumor necrosis factor alpha. These data indicate that AngIV could be involved in the vascular inflammatory response. Thus, in endothelial cells and VSMC, AngIV up-regulates plasminogen activator inhibitor-1 expression and could participate in thrombus formation. These results reveal novel concepts of RAS in the cardiovascular system, suggesting that AngIV could play an active role in vascular diseases.