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Tadeusz Malinski

Tadeusz Malinski

Distinguished Professor

Title: Nitric oxide/peroxynitrite imbalance in dysfunctional endothelium – Clinical implications

Biography

Biography: Tadeusz Malinski

Abstract

A dysfunctional endothelium is a common denominator of several cardiovascular diseases, including: hypertension, atherosclerosis, heart failure, diabetes, obesity and aging. Normal functioning endothelium mainly produces cytoprotective vasorelaxant, nitric oxide (NO) and traces of the cytotoxic vasoconstrictor, peroxynitrite (ONOO-). However, in dysfunctional endothelium, these proportions are reversed. The recent development of nanomedical systems allows for the simultaneous measurements, in situ, of small biomolecules like NO, ONOO- and superoxide (O2- in single a cell. NO is produced from L-arginine and O2 by a dimeric form of endothelial nitric oxide synthase (eNOS). However, destabilized/uncoupled eNOS dimer in dysfunctional endothelium can concomitantly produce O2- and NO. NO is a rapid scavenger of O2- to generate ONOO-, one of the most powerful oxidants in the cardiovascular system. ONOO- can also trigger a cascade of events leading to nitrosylation, nitration, apoptosis, necrosis,lipid peroxidation, enzyme inactivation and DNA modification. Using nanosensors, we found that absolute values of NO and ONOO- concentrations do not necessarily reflect the efficiency of the cardiovascular system. We observed that the balance between the concentrations of NO, [NO], and ONOO-, [ONOO-], was a more accurate metric. This balance between [NO]/[ONOO-] in functional endothelium varies between 2 and 6. However, if this balance falls below 1.0, it is usually associated with severe endothelial dysfunction in a diseased state. These nanomedical measurements of the [NO]/[ONOO-] balance/imbalance in a single endothelial cell can be used for the early diagnosis of cardiovascular dysfunction, as well as the design of early pharmacological intervention to restore endothelial function. The early diagnosis of the adverse balance of [NO]/[ONOO-] can be partially reversed with treatments of L-arginine, vitamin D3, nitroso albumin, and also by statins, β-blockers and some ACE inhibitors.