Much More than a Cardiotonic Steroid: Modulation of Inflammation by Ouabain

Abstract

Since the discovery of ouabain as a cardiotonic steroid hormone present in higher mammals, research about it has progressed rapidly and several of its physiological and pharmacological effects have been described. Ouabain can behave as a stress hormone and adrenal cortex is its main source. Direct effects of ouabain are originated due to the binding to its receptor, the Na+/K+-ATPase, on target cells. This interaction can promote Na+ transport blockade or even activation of signaling transduction pathways (e.g., EGFR/Src-Ras-ERK pathway activation), independent of ion transport. Besides the well-known effect of ouabain on the cardiovascular system and blood pressure control, compelling evidence indicates that ouabain regulates a number of immune functions. Inflammation is a tightly coordinated immunological function that is also affected by ouabain. Indeed, this hormone can modulate many inflammatory events such as cell migration, vascular permeability, and cytokine production. Moreover, ouabain also interferes on neuroinflammation. However, it is not clear how ouabain controls these events. In this brief review, we summarize the updates of ouabain effect on several aspects of peripheral and central inflammation, bringing new insights into ouabain functions on the immune system.

Na+, K+-ATPase α Isoforms and Endogenous Cardiac Steroids in Prefrontal Cortex of Bipolar Patients and Controls

“…To this end, studies in recent years have focused on the involvement of additional neurotransmitter/neuromodulators systems [63][64][65], mitochondrial function [66], and inflammation [67] in the etiology of BD. It is well established that Na + , K + -ATPase and ECS affect all these systems: They are involved in neurotransmitter release and reuptake [10,68], mitochondrial function [69], and inflammation [70]. Hence, the increase in the α2 and α3 isoforms of the Na + , K + -ATPase and the decrease in MBG in the PFC of BD patients, as found in this study, may be an intimate part of the molecular mechanisms of BD.…”

Ouabain Protects Mice Against Lipopolysaccharide-Induced Acute Lung Injury

“…However, studies have shown that ouabain induced lung inflammation and cytokines production, which may be associated with the differences on the dose and route of administration [ 24 ]. Although studies have shown that ouabain has a proinflammatory effect, more researches have focused on the inhibitory effect of ouabain on inflammation [ 25 ]. Therefore, we adopted LPS-induced ALI in our study to better understand the immunomodulatory effect of ouabain.…”

Ouabain Suppresses IL-6/STAT3 Signaling and Promotes Cytokine Secretion in Cultured Skeletal Muscle Cells

“…Cardiotonic steroids, whose endogenous secretion is believed to be regulated by the sympathoadrenergic system, the adrenocorticotropic hormone, and angiotensin II ( Laredo et al, 1995 , 1997 ; Bauer et al, 2005 ), may have an important role in regulation of Na + homeostasis, arterial blood pressure, as well as the stress and immune responses ( Foey et al, 1997 ; Fedorova et al, 2001 ; Berendes et al, 2003 ; Blaustein et al, 2012 ; Cavalcante-Silva et al, 2017 ). As estimated by an ouabain immunoassay, plasma concentrations of CTS are markedly increased during exercise ( Bauer et al, 2005 ), but their physiological role under these conditions has not been established.…”