Many experimental data have suggested that the renin-angiotensin system participates in immune and inflammatory responses. Angiotensin II is involved in several steps of the inflammatory process: mononuclear cells respond to angiotensin II stimulation (cell proliferation and chemotaxis); angiotensin II regulates the recruitment of proinflammatory cells into the site of injury (mediated by the expression of vascular permeability factors, adhesion molecules and chemokines by resident cells); inflammatory cells can produce angiotensin II, and might therefore contribute to the perpetuation of tissue damage. In this review, we summarize the proinflammatory properties of angiotensin II, to demonstrate the novel role of this vasoactive peptide as a true cytokine. We will show the information obtained as a result of the pharmacological blockade of the renin angiotensin system, which has demonstrated that this system is involved in immune and inflammatory diseases. In this aspect, we discuss the molecular mechanism of angiotensin II-induced tissue damage, as well as its contribution to the pathogenesis of several diseases, including atherosclerosis, hypertension and renal damage, showing that angiotensin II plays an active role in the inflammatory response of these diseases.

—Nuclear factor-κB (NF-κB) regulates many genes involved in vascular physiopathology. We have previously observed in vivo NF-κB activation in injured vessels that diminished by angiotensin-converting enzyme inhibition. In the present work, we investigated the effect of angiotensin II (Ang II) on NF-κB activity in rat vascular smooth muscle cells, evaluating the molecular mechanisms and the specific receptor subtype involved. Ang II increased NF-κB DNA binding (5-fold, 10⁻⁹mol/L at 1 hour; electrophoretic mobility shift assay), nuclear translocation of p50/p65 subunits, and cytosolic inhibitor κBα (IκBα) degradation. Ang II elicited NF-κB–mediated transcription (transfection of a reporter gene) and expression of NF-κB–related genes (monocyte chemoattractant protein-1 and angiotensinogen). AT₁(DUP753) and AT₂(PD123319 andCGP42112) receptor antagonists inhibited Ang II–induced NF-κB DNA binding in a dose-dependent manner (≈85% for each one; 10⁻⁵mol/L at 1 hour). The AT₂agonistp-aminophenylalanine⁶–Ang II augmented NF-κB binding (4.6-fold, 10⁻⁹mol/L at 1 hour), p65 nuclear levels, and transcription of an NF-κB reporter gene. AT₁antagonist markedly inhibited NF-κB–mediated transcription and gene expression. Some differences between AT₁/AT₂intracellular signals were found. Antioxidants and ceramide inhibitors, but not protein kinase C inhibitors, diminished NF-κB activation elicited by both Ang II and the AT₂agonist, while tyrosine kinase inhibitors only decreased Ang II–induced NF-κB activity. Our results demonstrate that Ang II activates NF-κB via AT₁and AT₂, although NF-κB–mediated transcription occurred mainly through AT₁. Both receptors share some signaling pathways (oxygen radicals and ceramide); however, tyrosine kinases only participate in AT₁/NF-κB responses. These data provide novel insights into Ang II actions, suggesting a potential implication of the AT₂in the pathobiology of vascular cells.

The renin-angiotensin system (RAS) has emerged as one of the essential links in the pathophysiology of vascular disease. Angiotensin (Ang) II, the main peptide of the RAS, was considered as a vasoactive hormone, but in the past years, this view has been modified to a growth factor that regulates cell proliferation/apoptosis and fibrosis. Recently, this view has been enlarged with a novel concept: Ang II participates in the inflammatory response, acting as a proinflammatory mediator. In resident vascular cells, Ang II produces chemokines, cytokines, and adhesion molecules, which contribute to the migration of inflammatory cells into the tissue injury. Ang II is also a chemotactic and mitogenic factor for mononuclear cells. The molecular mechanisms of Ang II–induced vascular damage are mediated by the activation of transcription factors, redox signaling systems, and production of endogenous growth factors. In addition, other components of the RAS could also be involved in the pathogenesis of cardiovascular diseases. The Ang II degradation product Ang III shares some of its properties with Ang II, including chemotaxis and production of growth factors and chemokines. All these data clearly demonstrate that Ang II is a true cytokine, show the complexity of the RAS in pathological processes, and provide some mechanistic responses of the beneficial effects of the treatment with RAS blockers in cardiovascular diseases.

Diabetic cardiomyopathy (DCM) is a cardiac dysfunction which affects approximately 12% of diabetic patients, leading to overt heart failure and death. However, there is not an efficient and specific methodology for DCM diagnosis, possibly because molecular mechanisms are not fully elucidated, and it remains asymptomatic for many years. Also, DCM frequently coexists with other comorbidities such as hypertension, obesity, dyslipidemia, and vasculopathies. Thus, human DCM is not specifically identified after heart failure is established. In this sense, echocardiography has been traditionally considered the gold standard imaging test to evaluate the presence of cardiac dysfunction, although other techniques may cover earlier DCM detection by quantification of altered myocardial metabolism and strain. In this sense, Phase-Magnetic Resonance Imaging and 2D/3D-Speckle Tracking Echocardiography may potentially diagnose and stratify diabetic patients. Additionally, this information could be completed with a quantification of specific plasma biomarkers related to related to initial stages of the disease. Cardiotrophin-1, activin A, insulin-like growth factor binding protein-7 (IGFBP-7) and Heart fatty-acid binding protein have demonstrated a stable positive correlation with cardiac hypertrophy, contractibility and steatosis responses. Thus, we suggest a combination of minimally-invasive diagnosis tools for human DCM recognition based on imaging techniques and measurements of related plasma biomarkers.