Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

Abstract

Significance: Aerobic organisms must exist between the dueling biological metabolic processes for energy and respiration and the obligatory generation of reactive oxygen species (ROS) whose deleterious consequences can reduce survival. Wide fluctuations in harmful ROS generation are circumvented by endogenous countermeasures (i.e., enzymatic and nonenzymatic antioxidants systems) whose capacity decline with aging and are enhanced by disease states. Recent Advances: Substantial efforts on the cellular and molecular underpinnings of oxidative stress has been complemented recently by the discovery that reductive stress similarly predisposes to inheritable cardiomyopathy, firmly establishing that the biological extremes of the redox spectrum play essential roles in disease pathogenesis. Critical Issues: Because antioxidants by nutritional or pharmacological supplement to prevent or mitigate disease states have been largely disappointing, we hypothesize that lack of efficacy of antioxidants might be related to adverse outcomes in responders at the reductive end of the redox spectrum. As emerging concepts, such as reductive, as opposed, oxidative stress are further explored, there is an urgent and critical gap for biochemical phenotyping to guide the targeted clinical applications of therapeutic interventions. Future Directions: New approaches are vitally needed for characterizing redox states with the long-term goal to noninvasively assess distinct clinical states (e.g., presymptomatic, end-stage) with the diagnostic accuracy to guide personalized medicine.

Redox balance and cardioprotection

“…The notion that reductive stress predisposes to cardiomyopathy as much as oxidative stress is gaining ground among biologists. Due to space constrain we cannot consider the reductive stress issue here but the reader is kindly redirect to a recent review on this topic [27].…”

Targeting the Ubiquitin-Proteasome System in Heart Disease: The Basis for New Therapeutic Strategies

“…However, activation of CryAB in PKN transgenic mice provides a link to investigations in DRC, suggesting that a CryAB missense mutation overloads the capacity of regular UPS function (27). Thus, activation of CryAB may relieve the workload of the UPS by its chaperone activity (19).…”

Proteotoxicity and Cardiac Dysfunction

“…At this point, it is clear that protein misfolding in the heart can be either extracellular, as is the case for transthyretin amyloidosis, 24,96 or intracellular as occurs in the Desmin Related (Cardio)Myopathies (DRM). 97 Diverse pathogenic insults can also lead to proteotoxicity including, but not limited to: chronic synthesis of a compromised protein, 87 organ-specific pathogenic stimuli such as cardiac infarction, pressure overload-induced hypertrophy or the production of reactive oxygen species [98][99][100] and generalized systemic insults such as diabetes [101][102][103] or aging. 4 These different primary etiologies can have multiple effects on either the production of misfolded proteins, their accumulation in critical cellular compartments or the cell's machinery for decreasing the misfolded protein/protein aggregate load.…”