Abnormal Ca²⁺Cycling in Failing Ventricular Myocytes: Role of NOS1-Mediated Nitroso-Redox Balance

Abstract

Significance: Heart failure (HF) results from poor heart function and is the leading cause of death in Western society. Abnormalities of Ca 2+ handling at the level of the ventricular myocyte are largely responsible for much of the poor heart function. Recent Advances: Although studies have unraveled numerous mechanisms for the abnormal Ca 2+ handling, investigations over the past decade have indicated that much of the contractile dysfunction and adverse remodeling that occurs in HF involves oxidative stress. Critical Issues: Regrettably, antioxidant therapy has been an immense disappointment in clinical trials. Thus, redox signaling is being reassessed to elucidate why antioxidants failed to treat HF. Future Directions: A recently identified aspect of redox signaling (specifically the superoxide anion radical) is its interaction with nitric oxide, known as the nitroso-redox balance. There is a large nitroso-redox imbalance with HF, and we suggest that correcting this imbalance may be able to restore myocyte contraction and improve heart function.

Obligatory role of neuronal nitric oxide synthase in the heart's antioxidant adaptation with exercise

“…These mice have a negative shift of the nitroso-redox balance, and it’s known that the nitroso-redox signaling network modulates multiple protein targets (e.g., SERCA, RyR2, etc.) involved with contraction [46]. In addition to modulating contractile proteins, there may also be cardiac structural abnormalities.…”

Insulin‐like growth factor 1 prevents diastolic and systolic dysfunction associated with cardiomyopathy and preserves adrenergic sensitivity

“…As BH4 levels decrease, NOS becomes uncoupled from NO production and favours the production of ROS, such as superoxide (Alkaitis & Crabtree ). This increase in cellular ROS leads to cell damage and promotes the oxidation of many key proteins involved in excitation–contraction coupling in the heart, supplying an arrhythmogenic substrate (Ziolo & Houser , Roof et al . ).…”

“…As BH4 levels decrease, NOS becomes uncoupled from NO production and favours the production of ROS, such as superoxide (Alkaitis & Crabtree 2012). This increase in cellular ROS leads to cell damage and promotes the oxidation of many key proteins involved in excitation-contraction coupling in the heart, supplying an arrhythmogenic substrate (Ziolo & Houser 2014, Roof et al 2015. While ROS production per se was not measured here, maintained levels of BH4 would be expected to recouple NOS to NO production and are indicated to be cardioprotective (Szelenyi et al 2015).…”

Novel Perspectives in Redox Biology and Pathophysiology of Failing Myocytes: Modulation of the Intramyocardial Redox Milieu for Therapeutic Interventions—A Review Article from the Working Group of Cardiac Cell Biology, Italian Society of Cardiology

“…Superoxide anion (O 2 − ) can react with NO, forming reactive species such as peroxynitrite, producing abnormalities in the nitroso-redox balance and further myocardial derangements [ 26 , 30 ]. Importantly, in cardiomyocytes NO mediates S-nitrosylation of specific cysteines [ 33 , 75 ], with effects on Ca 2+ fluxes and EC coupling [ 33 , 76 ], but high levels of O 2 − can inhibit physiologic S-nitrosylation. High O 2 − concentrations interact with NO to form peroxynitrite that can produce numerous cytotoxic effects that may alter excitation-contraction coupling [ 26 , 77 , 78 ].…”