Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

Abstract

e NO/ONOO − cycle is a primarily local biochemical/physiological vicious cycle that appears to cause a series of chronic in�ammatory diseases. is paper focuses on whether the cycle causes pulmonary arterial hypertension (PAH) when located in the pulmonary arteries. e cycle involves 12 elements, including superoxide, peroxynitrite (ONOO − ), nitric oxide (NO), oxidative stress, NF-B, in�ammatory cytokines, iNOS, mitochondrial dysfunction, intracellular calcium, tetrahydrobiopterin depletion, NMDA activity, and TRP receptor activity. 10 of the 12 are elevated in PAH (NMDA?, NO?) and 11 have documented causal roles in PAH. Each stressor that initiates cases of PAH acts to raise cycle elements, and may, therefore, initiate the cycle in this way. PAH involves a primarily local mechanism as required by the cycle and the symptoms and signs of PAH are generated by elements of the cycle. Endothelin-1, which acts as a causal factor in PAH, acts as part of the cycle; its synthesis is stimulated by cycle elements, and it, in turn, increases each element of the cycle. is extraordinary �t to the principles of the NO/ONOO − cycle allows one to conclude that PAH is a NO/ONOO − cycle disease, and this �t supports the cycle as a ma�or paradigm of chronic in�ammatory disease.

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

“…[1] with permission). A – E differ from one another in which arrows are dashed, so that the constituent cycles that make up the overall NO/ONOO-cycle may be considered independently of each other.…”

“…What is now known as the NO/ONOO-cycle has gone through several iterations [ 1 – 9 ], with the most recent version diagrammed in Figure 1A–E [ 1 ]. Subfigures A to E in Figure 1 are identical to each other, except that certain arrows in each are dashed, so that each of these, as discussed below, is a vicious cycle on its own.…”

“…The intramitochondrial sequence is often initiated by NO, but involves superoxide, ONOO-, inactivation of mitochondrial proteins and oxidation of the cardiolipin in the inner membrane in the mitochondrion. The extramitochondrial sequence is triggered by ONOO-, leading to major stimulation of poly(ADP-ribose) polymerase (often designated PARP or PARS) [ 1 – 3 ], leading to the depletion of the PARP enzyme substrate NAD and consequently also its reduced form, NADH. NADH is the most important source of reductants entering the mitochondrion and is essential, therefore for effective oxidative phosphorylation; NADH depletion, therefore, leads to mitochondrial dysfunction and ATP depletion.…”

“…The NO/ONOO-cycle is a primarily local, biochemical vicious cycle, which depending on where it is located in the body, may be the cause of various chronic inflammatory diseases [ 1 – 8 ]. Various diseases have been argued to be possible NO/ONOO-cycle diseases, and, for many of them, the cases made have been relatively superficial.…”

“…Most of these possible NO/ONOO-cycle diseases are probably located primarily in regions of the central nervous system [ 2 – 8 ]. However, a recent, very detailed case, argues that pulmonary arterial hypertension is a probable NO/ONOO-cycle disease [ 1 ], suggesting that other types of cardiovascular diseases may also be candidates for being caused by this mechanism.…”