The molecular mechanisms associated with the physiological responses to inflammation and oxidative stress in cardiovascular diseases

Abstract

The complex physiological signal transduction networks that respond to the dual challenges of inflammatory and oxidative stress are major factors that promote the development of cardiovascular pathologies. These signaling networks contribute to the development of age-related diseases, suggesting crosstalk between the development of aging and cardiovascular disease. Inhibition and/or attenuation of these signaling networks also delays the onset of disease. Therefore, a concept of targeting the signaling networks that are involved in inflammation and oxidative stress may represent a novel treatment paradigm for many types of heart disease. In this review, we discuss the molecular mechanisms associated with the physiological responses to inflammation and oxidative stress especially in heart failure with preserved ejection fraction and emphasize the nature of the crosstalk of these signaling processes as well as possible therapeutic implications for cardiovascular medicine.

Keywords: Cardiovascular diseases; Heart failure; Molecular mechanisms; Proteins modification; Signaling pathways.

Fig. 1

Mechanisms, sources, and implications of oxidative stress in cardiovascular disease and heart failure. Aging, genetic predisposition, conventional risk factors, and environmental factors can induce oxidative stress, where NADPH, NOX, and uncoupled NOS are dominant sources of ROS. When the generation of ROS is greater than the antioxidative capacity, then cell damage and endothelial dysfunction arise due to increased ROS level. As a consequence, oxidation of mitochondrial NADPH, H2O2 is increased, which plays a causal role in contractile dysfunction, arrhythmia, and ultimately maladaptive cardiac remodeling through hypertrophy and cell death. Abbreviations: H2O2, hydrogen peroxide; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthase; NOX, nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase); ROS, reactive oxygen species; IL, interleukin; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; TNF-α, tumor necrosis factor-α

Fig. 2

Scheme for the signaling pathways of cardiomyocyte in diseased heart under oxidative (right) and healthy (left) conditions. A Represents a heart under oxidative condition with impaired endothelial function via increased inflammatory cytokines and oxidative stress. B Represents a healthy condition showing a normal endothelial function via normal/low inflammatory cytokines and oxidative stress (green arrow pointing upwards means increase and green arrow pointing down means decrease). Abbreviations: cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; PKG, protein kinase G; H₂O₂, hydrogen peroxide; NO, nitric oxide; ONOO-, peroxynitrite; PKG, protein kinase G; PKA, protein kinase A; PKC, protein kinase C; CaMKII, calcium calmodulin–dependent kinase II; MAPK, mitogen-activated protein kinase; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; GSH, reduced glutathione; GSSG, oxidized glutathione

Fig. 3

Thiol modifications of proteins and mechanisms of titin-based passive tension modulation by oxidative stress–induced titin modifications. A Formation of sulfenic acid from the reaction of H₂O₂ with protein thiolates. This formation leads to different protein modifications. In proteins without a second sulfhydryl, the sulfenic acid (–SOH) may be stabilized or will generate oxidized sulfinic (–SOOH) and sulfonic acid derivatives due to its reaction with ROS. Otherwise, a disulfide bond can form between the two sulfur atoms (–S–S–). Lastly, the sulfenated cysteinyl residue can react with glutathione (GSH), leading to a mixed disulfide. B Formation of intramolecular disulfide bonds within the titin-N2Bus when exposed to oxidative stress, which then increases titin-based stiffness in cardiomyocytes. C Ig domain unfolding due to sarcomere stretching causes exposure of hidden (“cryptic”) cysteines in Ig domains, which can become S-glutathionylated under oxidative conditions. This modification prevents Ig domain refolding, resulting in decreased titin-based stiffness. D Isomerization of disulfide bonds of the cysteine triad in titin Ig domains can occur under oxidative conditions. This modification leads to increased titin based stiffness

Fig. 4

Scheme for the signaling pathways of endothelial cell in diseased heart under oxidative (right) and healthy (left) conditions. A Represents a heart under oxidative condition with impaired endothelial function via increased inflammatory cytokines and oxidative stress (red arrow pointing upwards means increase and red arrow pointing down means decrease). B Represents a healthy condition showing a normal endothelial function via normal/low inflammatory cytokines and oxidative stress (green arrow pointing upwards means increase and green arrow pointing down means decrease). Abbreviations: H₂O₂, hydrogen peroxide; ICAM-1, intercellular cell adhesion molecule-1; IL-6, interleukin-6; NO, nitric oxide; NOX2, NADPH phagocyte oxidase isoform; ONOO-, peroxynitrite; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; TNF-α, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1; P-eNOS, phospho-endothelial nitric oxide synthase