Hypothalamic-Pituitary-Adrenal Axis Modulation of Glucocorticoids in the Cardiovascular System

Abstract

The collective of endocrine organs acting in homeostatic regulation-known as the hypothalamic-pituitary-adrenal (HPA) axis-comprises an integration of the central nervous system as well as peripheral tissues. These organs respond to imminent or perceived threats that elicit a stress response, primarily culminating in the release of glucocorticoids into the systemic circulation by the adrenal glands. Although the secretion of glucocorticoids serves to protect and maintain homeostasis in the typical operation at baseline levels, inadequate regulation can lead to physiologic and psychologic pathologies. The cardiovascular system is especially susceptible to prolonged dysregulation of the HPA axis and glucocorticoid production. There is debate about whether cardiovascular health risks arise from the direct detrimental effects of stress axis activation or whether pathologies develop secondary to the accompanying metabolic strain of excess glucocorticoids. In this review, we will explore the emerging research that indicates stress does have direct effects on the cardiovascular system via the HPA axis activation, with emphasis on the latest research on the impact of glucocorticoids signaling in the vasculature and the heart.

Keywords: cardiomyocytes; glucocorticoid receptor; glucocorticoids; heart; hypothalamic-pituitary-adrenal axis; mineralocorticoid receptor; smooth muscle cells; vascular endothelial cells.

Figure 1

The activation of the hypothalamic-pituitary-adrenal (HPA) axis. Response to a stress stimulus is routed to the hypophysiotropic neurons in the paraventricular nucleus (PVN) of the hypothalamus. These neurosecretory cells release corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), which travel through the median eminence and hypophyseal portal vessels. Once CRH reaches the anterior pituitary, it binds CRF type 1 receptors of pituitary corticotroph cells. Adrenocorticotropic hormone (ACTH) is released into circulation, binds its receptors in the zona fasiculata of the adrenal cortex, and causes release of glucocorticoids. Glucocorticoids in circulation act on target cardiovascular tissues (including, the heart, the vasculature, adipose tissue and muscle) then feedback to the level of the central nervous system (CNS) to inhibit activation of the HPA axis.

Figure 2

The direct and indirect effects of glucocorticoids on the vascular endothelium. glucocorticoids, through glucocorticoid receptors (GRs), regulate the expression of molecules critical to maintain the endothelium structural and functional properties. Among these molecules are adhesion molecules (VCAM-1, ICAM-1 and E selectin), pro-inflammatory cytokine and chemokine production (IL-6, IL-17F, CXCL8 (IL-8), and CCL2 (MCP-1)), vasodilators nitric oxide and vasoconstrictors angiotensin II and endothelin I [54,55,56,57,58,59]. Via the regulation of these mediators, GR exerts effects on blood pressure regulation, endothelial cell proliferation, viability, migration, cell death and the expression of inflammatory mediators in response to injury or infection. Dashed arrow: Effects of GR on the vasculature; Up arrow: up-regulation; Down Arrow: down-regulation.

Figure 3

The physiological effects of glucocorticoids in the heart. Glucocorticoid treatment of cardiomyocytes has both positive and negative effects (right panel). In the setting of ischemia/reperfusion glucocorticoid treatment protects the cells against apoptosis by regulating the expression of lipocalin-type prostaglandin D synthase (L-PGDS), which induces prostaglandin biosynthesis, limiting the inflammatory response and tissue damage [68]. Also, glucocorticoids protect cardiomyocytes from apoptosis in response to starvation ((−) serum); however, glucocorticoids also lead to hypertrophy if cardiomyocytes are cultured in complete media ((+) serum) [69]. GR can also regulate pro-survival genes, for example, krüppel like factor (KLF)-13 [70], a zinc finger transcription factor involved in cardiac development. GR via KLF-13 regulation protects cardiomyocytes from DNA damage and cell death induced by cobalt (II) chloride hexahydrate (CoCl₂·6H₂O) and the antineoplastic drug doxorubicin [70]. Data from in vivo studies have shown that glucocorticoids have direct and indirect effects in the heart (left panel). Studies on long-term adrenalectomized mice have demonstrated that glucocorticoid signaling through GR exerts important effects on left ventricular function and cardiac gene expression, while aldosterone signaling via mineralocorticoid receptors (MR) appears to play a predominant effect in the modulation of cardiac electrical activity [50]. Gain/loss of function studies employing transgenic mouse models have demonstrated that glucocorticoids via cardiomyocyte GR are critical for normal physiology and play a role in maintaining cardiac electrical properties [72,78]. The role of MR in the heart has been demonstrated, employing a similar approach. MR activation under pathological conditions is detrimental and promotes adverse remodeling characterized by inflammation and fibrosis [75]. In contrast, loss of MR function leads to the attenuation of cardiac dysfunction, cardiomyocyte death and adverse remodeling in ischemia models [79,80,81,82].