The NO/ONOO-Cycle as the Central Cause of Heart Failure

Abstract

The NO/ONOO-cycle is a primarily local, biochemical vicious cycle mechanism, centered on elevated peroxynitrite and oxidative stress, but also involving 10 additional elements: NF-κB, inflammatory cytokines, iNOS, nitric oxide (NO), superoxide, mitochondrial dysfunction (lowered energy charge, ATP), NMDA activity, intracellular Ca2+, TRP receptors and tetrahydrobiopterin depletion. All 12 of these elements have causal roles in heart failure (HF) and each is linked through a total of 87 studies to specific correlates of HF. Two apparent causal factors of HF, RhoA and endothelin-1, each act as tissue-limited cycle elements. Nineteen stressors that initiate cases of HF, each act to raise multiple cycle elements, potentially initiating the cycle in this way. Different types of HF, left vs. right ventricular HF, with or without arrhythmia, etc., may differ from one another in the regions of the myocardium most impacted by the cycle. None of the elements of the cycle or the mechanisms linking them are original, but they collectively produce the robust nature of the NO/ONOO-cycle which creates a major challenge for treatment of HF or other proposed NO/ONOO-cycle diseases. Elevated peroxynitrite/NO ratio and consequent oxidative stress are essential to both HF and the NO/ONOO-cycle.

Influence of cardiac resynchronization therapy on oxidative stress markers in patients with chronic heart failure

“…One problem with scavenging-type antioxidants is that secondary radicals derived from them can often do biologic damage themselves. Increased production of ROS observed in HF derives from several pathogenetic disturbances featuring catecholamine auto-oxidation, mitochondrial leak, recurrent ischemic episodes, and post reperfusion microcirculatory damage, as well as from the involvement of biologically active substances such as angiotensin II, xanthine oxidase, nitric oxide synthase and cytokines [16].…”

“…One of the most popular products in laboratory practice is the thiobarbituric acid-reactive substances (TBARS). TBARS as important lipid peroxidation products, with their main component -malondialdehyde (MDA), are indicators of ROS [16,20].…”

“…The pivotal neurohumoral mechanisms include activation of the renin-angiotensin-aldosterone system and the catecholaminergic nervous system [15]. One of the mechanisms of less established pathophysiologic role in CHF in humans is oxidative stress in the failing heart [16].…”

Putative Prophylaxes of Aloe Vera Juice with L-arginine to Chronic Fatigue Syndrome

“…None of the elements of the cycle or the mechanisms linking them are original, but they collectively produce the robust nature of the NO/ONOO-cycle diseases. Elevated peroxynitrite/NO ratio and consequent oxidative stress are essential to both HF and the NO/ ONOO-cycle [26] . Ohtsuka Y. and Nakaya J., studied 16 elderly patients (mean±SD age of 79 ± 7 years; 13 women and 3 men) with cerebrovascular disease who had been living in a nurcing home for 2 to 4 years.…”

Low Nasal NO in Congenital Heart Disease With Systemic Right Ventricle and Postcardiac Transplantation

“…Because NO is an important mediator of coronary microcirculatory function,9 and its bioavailability may be crucial to the development of heart failure,10, 11 this suggests NO measurements may have clinical utility as a biomarker for assessing heart failure risks. However, NO measurement in blood is difficult because of NO's extremely short half‐life (<2 ms) 12.…”