Glucocorticoid Signaling and the Aging Heart

Abstract

A decline in normal physiological functions characterizes the aging process. While some of these changes are benign, the decrease in the function of the cardiovascular system that occurs during aging leads to the activation of pathological processes associated with an increased risk for heart disease and its complications. Imbalances in endocrine function are also common occurrences during the aging process. Glucocorticoids are primary stress hormones and are critical regulators of energy metabolism, inflammation, and cardiac function. Glucocorticoids exert their actions by binding the glucocorticoid receptor (GR) and, in some instances, to the mineralocorticoid receptor (MR). GR and MR are members of the nuclear receptor family of ligand-activated transcription factors. There is strong evidence that imbalances in GR and MR signaling in the heart have a causal role in cardiac disease. The extent to which glucocorticoids play a role in the aging heart, however, remains unclear. This review will summarize the positive and negative direct and indirect effects of glucocorticoids on the heart and the latest molecular and physiological evidence on how alterations in glucocorticoid signaling lead to changes in cardiac structure and function. We also briefly discuss the effects of other hormones systems such as estrogens and GH/IGF-1 on different cardiovascular cells during aging. We will also review the link between imbalances in glucocorticoid levels and the molecular processes responsible for promoting cardiomyocyte dysfunction in aging. Finally, we will discuss the potential for selectively manipulating glucocorticoid signaling in cardiomyocytes, which may represent an improved therapeutic approach for preventing and treating age-related heart disease.

Keywords: aging; cardiomyocytes; glucocorticoids; heart; myocardium.

Figure 1

Regulation of glucocorticoid synthesis and secretion by the hypothalamic-pituitary-adrenal axis. Exposure to stressors and changes in our daily cycle (circadian rhythms) stimulate the parvocellular neurons within the paraventricular nucleus of the hypothalamus to release corticotropin releasing hormone (CRH). CRH then triggers the secretion of the adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. ACTH then binds to its receptors (melanocortin receptor 2, MC2R) located on the cortex of the adrenal gland. ACTH binding to MC2R leads to the activation of adenylyl cyclase (AC) and the production of intracellular cyclic adenosine monophosphate (cAMP). cAMP then activates protein kinase A (PKA), which then phosphorylates cAMP response element-binding protein (CREB), which then promotes steroidogenic gene expression (Cytochrome P450 Family 11 Subfamily B Member, CYPB2, and the steroidogenic acute regulatory protein, StAR) that leads to the transport of cholesterol (imported from the blood into the cortical cells via the scavenger receptor type B class 1, SARB1) into the mitochondria, where glucocorticoids are synthesized (steroidogenesis) by the action of mitochondrial and smooth endoplasmic reticulum enzymes. The biologically active form of the glucocorticoid is the unbound cortisol that can be converted to the inactive form, cortisone by type 2 11β-hydroxysteroid dehydrogenase. Type 1 11β-hydroxysteroid dehydrogenase converts the cortisone to cortisol. Homeostasis in glucocorticoids synthesis and secretion is maintained by the negative feedback loop suppressing ACTH levels in the anterior pituitary and CRH levels in the hypothalamus.

Figure 2

Physiological glucocorticoid effects. Glucocorticoids exert direct actions in major organ systems of the human body. Their effects range from modulation of the inflammatory and immune response to the regulation of glucose and lipid metabolism in different tissues. Glucocorticoid signaling plays an essential role on the cardiovascular system. In normal physiology, glucocorticoids exert cardioprotective and anti-inflammatory effects, and have an essential role in controlling blood pressure and cardiac function.

Figure 3

Schematic representation of the phenotypes of transgenic mice targeting GR in cardiomyocytes. Shown are the major morphological and functional phenotypes associated with GR overexpression (GR+), GR inactivation (GR–), and GR and MR inactivation (GR/MR–) in the whole heart, vascular smooth muscle cells (VSMC), and cardiomyocytes.