Effects of angiotensin II and insulin on ERK1/2 activation in fibroblasts from hypertensive patients

• Published in: American journal of hypertension 2004-07, Vol.17 (7), p.604-610
• Main Authors: Sartori, Michelangelo, Ceolotto, Giulio, Papparella, Italia, Baritono, Elisabetta, Ciccariello, Laura, Calò, Lorenzo, Leoni, Matteo, Semplicini, Andrea
• Format: Article
• Language: English
• Subjects: Adult; angiotensin II; Angiotensin II - administration & dosage; Angiotensin II - therapeutic use; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Biomarkers - blood; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; diabetes; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; Humans; hypertension; Hypertension - drug therapy; Hypertension - metabolism; Hypertension - physiopathology; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - therapeutic use; insulin; Insulin - administration & dosage; Insulin - therapeutic use; Insulin Resistance; Italy; Male; Medical sciences; Middle Aged; Mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 1 - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - drug effects; Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Phosphotransferases - drug effects; Phosphotransferases - metabolism; Receptor, Angiotensin, Type 1 - therapeutic use; signal transduction; Time Factors; Treatment Outcome; Vasoconstrictor Agents - administration & dosage; Vasoconstrictor Agents - therapeutic use
• ISSN: 0895-7061; 1879-1905; 1941-7225
• DOI: 10.1016/j.amjhyper.2004.02.017

Insulin resistance, a frequent finding in hypertensive patients, leads to accelerated cardiovascular damage. It has been suggested that a crosstalk between angiotensin II and insulin signaling pathways may provoke insulin resistance, and may contribute to the development of cardiovascular damage. To identify a common pathophysiologic pathway between metabolic disorders and cardiovascular remodeling, we investigated the effect of angiotensin II and insulin on extracellular signal regulated kinases 1 and 2 (ERK1/2), isoforms of mitogen-activated protein kinases (MAPK) involved in cellular proliferation and extracellular matrix deposition. Skin fibroblasts from normotensive subjects, insulin sensitive hypertensive subjects, and insulin resistant hypertensive subjects were cultured and used after four passages. The ERK1/2 expression and phosphorylation were measured by Western blot using specific antibodies, respectively anti-ERK1/2 and anti-pERK1/2. Expression of AT 1 receptor for angiotensin II was determined by reverse transcriptase–polymerase chain reaction in real time. The ERK1/2 were similarly expressed in skin fibroblasts from all groups; ERK1/2 phosporylation evoked by angiotensin II was significantly higher in fibroblasts from hypertensive patients in comparison to normotensive subjects, but the increase was observed only in insulin resistant hypertensive subjects. The effect of insulin on ERK1/2 phosphorylation was not significantly different in the three groups. Treatment with the combination of insulin and angiotensin II increased ERK1/2 phosphorylation to a greater extent in comparison to the single agonists in normotensive subjects and in insulin sensitive but not in insulin resistant hypertensive subjects. Angiotensin II stimulated ERK1/2 activation is increased in insulin resistant hypertensive subjects, and it may play a role in the pathogenesis of insulin resistance and accelerated cardiovascular damage.