Glucocorticoid signaling in the heart: A cardiomyocyte perspective

Abstract

Heart failure is one of the leading causes of death in the Western world. Glucocorticoids are primary stress hormones that regulate a vast array of biological processes, and synthetic derivatives of these steroids have been mainstays in the clinic for the last half century. Abnormal levels of glucocorticoids are known to negatively impact the cardiovascular system; however, surprisingly little is known about the direct role of glucocorticoid signaling in the heart. The actions of glucocorticoids are mediated classically by the glucocorticoid receptor (GR). In certain cells, such as cardiomyocytes, glucocorticoid occupancy and activation of the mineralocorticoid receptor (MR) may also contribute to the observed response. Recently, there has been a surge of reports investigating the in vivo function of glucocorticoid signaling in the heart using transgenic mice that specifically target GR or MR in cardiomyocytes. Results from these studies suggest that GR signaling in cardiomyocytes is critical for the normal development and function of the heart. In contrast, MR signaling in cardiomyocytes participates in the development and progression of cardiac disease. In the following review, we discuss these genetic mouse models and the new insights they are providing into the direct role cardiomyocyte glucocorticoid signaling plays in heart physiology and pathophysiology.

Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

“…In the heart, activation of both GR and MR has an impact on cardiac development, physiology and pathophysiology (reviewed in Oakley & Cidlowski 2015 and Richardson et al 2016). GR and MR are highly related and belong to the nuclear receptor family of transcriptional regulators (Biddie et al 2010), although some corticosteroid actions may be mediated by non-classical signalling through cell-surface receptors (Mihailidou & Funder 2005, Samarasinghe et al 2012).…”

Anti-inflammatory therapy in the treatment of cardiovascular diseases

“…An important role of GR in the maturation of cardiomyocytes and regulation of their function has been shown in a murine model [12]. In contrast, absence of this receptor is associated with developmental anomalies and myocardial dysfunction.…”

“…Based on the available studies, it has been postulated that use of selective MR antagonists together with GR agonists may lead to a significant progress in the treatment of cardiac disease in the future, but further studies are necessary to confirm these hypotheses [12]. In the past, use of GCS in acute myocardial infarction was associated with an increased risk of mechanical complications of infarction, including cardiac rupture.…”

Effects of Polybrominated Diphenyl Ethers on Rat and Human 11β-Hydroxysteroid Dehydrogenase 1 and 2 Activities

“…Glucocorticoids play many physiological and pharmacological roles in functions for mammals [1,2] . Glucocorticoids bind to the glucocorticoid receptor to regulate their target gene expressions.…”

“…[1,2-3 H]Corticosterone ( 3 H-CORT, specific activity, 40 Ci/ mmol) and [1,2,6, H(N)]-cortisol (specific activity, 70-100 Ci/ mmol) were purchased from Dupont-New England Nuclear (Boston, Mass., USA). [1,2-3 H]11dehydrocorticosterone ( 3 H-11DHC) and [1,2,6, H(N)]-cortisone were prepared from labeled 3 H-CORT or 3 H-cortisol as described earlier [14] . Cold CORT, 11DHC, cortisol, and cortisone were purchased from Steraloids (Wilton, NH).…”