The NO/ONOO-cycle as the central cause of heart failure.
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 Ca(2+), 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.
Biochemistry and Basic Medical Sciences, Washington State University, 638 NE 41st Ave., Portland, OR 97232-3312, USA. martin_pall@wsu.edu.
Martin L
ML
Pall
D019332:Endothelin-1 / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D019332:Endothelin-1; D017382:Reactive Oxygen Species; C066737:RHOA protein, human; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D020742:rhoA GTP-Binding Protein