Non-genomic effect of glucocorticoids on cardiovascular system

Abstract

Glucocorticoids (GCs) are essential steroid hormones for homeostasis, development, metabolism, and cognition and possess anti-inflammatory and immunosuppressive actions. Since glucocorticoid receptor II (GR) is nearly ubiquitous, chronic activation or depletion of GCs leads to dysfunction of diverse organs, including the heart and blood vessels, resulting predominantly from changes in gene expression. Most studies, therefore, have focused on the genomic effects of GC to understand its related pathophysiological manifestations. The nongenomic effects of GCs clearly differ from well-known genomic effects, with the former responding within several minutes without the need for protein synthesis. There is increasing evidence that the nongenomic actions of GCs influence various physiological functions. To develop a GC-mediated therapeutic target for the treatment of cardiovascular disease, understanding the genomic and nongenomic effects of GC on the cardiovascular system is needed. This article reviews our current understanding of the underlying mechanisms of GCs on cardiovascular diseases and stress, as well as how nongenomic GC signaling contributes to these conditions. We suggest that manipulation of GC action based on both GC and GR metabolism, mitochondrial impact, and the action of serum- and glucocorticoid-dependent kinase 1 may provide new information with which to treat cardiovascular diseases.

Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages

“…A wealth of recent investigations have indicated that nongenomic GC actions restrict the early/acute phase of inflammatory responses (3)(4)(5)(6)(7)(8)(9)(10). Consistent with these findings, we show that cotreatment with Dex and CpG inhibited phosphorylation of TAK1, IkBa, JNK, and p38 MAPK within 15-30 min of ligand challenge, indicating a new translation-independent mechanism of GC suppression (Fig.…”

“…In acute stress, mounting evidence suggests that nongenomic GC activities provide therapeutic benefits (6). The beneficial nongenomic GC effects have been implicated in asthma, allergic rhinitis, cardiovascular pathologies, and rheumatoid arthritis (7)(8)(9)(10). In fact, GC suppress aerosol-mediated allergic asthma within 10 min of challenge with allergen (11), and macrophage potency for phagocytosis and reactive oxygen species generation were inhibited within 30 min of GC treatment (12).…”

Stress, the Stress System and the Role of Glucocorticoids

“…Representative examples of non-genomic glucocorticoid actions are: (i) the immediate suppression of ACTH secretion from the anterior pituitary by glucocorticoids [30]; (ii) the glucocorticoid-induced rapid increase in the frequency of excitatory post-synaptic potentials in the hippocampus [31]; (iii) the rapid and transient decrease in blood pressure associated with a concomitant increase in coronary and cerebral blood flow in patients with myocardial infarction or stroke [32], and (iv) the rapid inhibition of T cell receptor signaling through disruption of the T cell receptor complex [33]. These actions are thought to be mediated by membrane-localized GRs, which, upon ligand binding, trigger the activation of kinase signaling cascades, such as the mitogen-activated protein kinase or the phosphatidylinositol 3-kinase pathways [26,27,28,29]. Although the downstream events of non-genomic glucocorticoid signal transduction have been partially elucidated, the origin and membrane localization mechanism(s) of the membrane GR still remain an enigma.…”

“…Apart from their short time frame, these glucocorticoid actions do not require hGRα-mediated transcription/translation, and thus are referred to as ‘non-genomic', and can occur in various systems, including the neuroendocrine, cardiovascular and immune systems [26,27,28,29]. Representative examples of non-genomic glucocorticoid actions are: (i) the immediate suppression of ACTH secretion from the anterior pituitary by glucocorticoids [30]; (ii) the glucocorticoid-induced rapid increase in the frequency of excitatory post-synaptic potentials in the hippocampus [31]; (iii) the rapid and transient decrease in blood pressure associated with a concomitant increase in coronary and cerebral blood flow in patients with myocardial infarction or stroke [32], and (iv) the rapid inhibition of T cell receptor signaling through disruption of the T cell receptor complex [33].…”

Cushing syndrome, metabolic syndrome and inflammation: a suggested way out

“…Their levels raise up to ten times the normal values in stressing contexts, in order to provide more blood and energy supply to cells and tissues (2,3). Glucocorticoids also act as potent anti-inflammatory agents stabilizing lysosomal membranes, inhibiting prostaglandins and leukotrienes synthesis, blocking the inflammatory response mediators and reducing vascular permeability, chemotactic activity and leukocycte diapedesis (4, 5).…”