IGF-1 &RAS in Development /Regression of Hypertrophy

Howard University, Washington DC

Investigators

Linked publications & trials

Abstract

Cardiac hypertrophy is a pathological state that can lead to heart failure. More than the quarter of US adult American population lives , whereby more than half of these cases are associated with cardiac hypertrophy. A universal electrophysiological finding in ventricular cells of hypertrophied heart is prolonged on the action potential duration (APD), which facilitates the propagation of re-entry arrhythmias and heart failure. The role of different ionic currents responsible for this APD lengthening is still debatable; mainly due to the fact and electrophysiological alterations are dependent on the etiology stage and model of hypertrophy and species. On the other hand, the renin-angiotensin system plays an important role in the regulation of cardiovascular tone and hypertrophy through its vasoactive component, angiotensin II (ANG II) mainly via its non-tyrosine kinase G-protein AT1 receptors. However, it is more evident that ANG II mitogenic effects are mediated essentially by the tyrosine kinase IGF-1 receptors through a cross talk with activated AT1 receptors. This proposal is intended to elucidate the modulation by ANG II and IGF-1 of potassium (IK1 and IK-ATP) and calcium (Ica,L) channels during the development and regression phases by (angiotensin-converting enzyme inhibitor (ACE-I) or AT1-antagonist treatment) of cardiac hypertrophy in the adult rat. The patch-clamp technique will be used to study channel activity, while the intracellular imaging technique with Fura-II will be used to monitor changes in intracellular calcium handling in isolated ventricular myocytes. Changes at the membrane level will be correlated to ANG II- and IGF-1-induced changes at 2nd messenger level (PKA, PKC, PI-3 kinase, and downstream tyrosine kinase and MAP kinase) during cardiac hypertrophy and after its regression by ACE-I or AT1-antagonist. The mitogenic effects of ANG II and its cross talk with IGF-1 signal transduction will be evaluated in association with the electrophysiological changes during both phases. Therefore, the effects of ANG II on Ica, L and [Ca2+]i as well as potassium currents (IK1 and IK-ATP) will be compared in the presence of varying IGF-1 concentrations. Thus, this project will identify and evaluate the signal transduction pathways mediating both ANG II and IGF-1 effects and the importance of the cross talk during the development and regression of cardiac hypertrophy.