Adrenal G Protein-Coupled Receptors and the Failing Heart: A Long-distance, Yet Intimate Affair

Abstract

:Systolic heart failure (HF) is a chronic clinical syndrome characterized by the reduction in cardiac function and still remains the disease with the highest mortality worldwide. Despite considerable advances in pharmacological treatment, HF represents a severe clinical and social burden. Chronic human HF is characterized by several important neurohormonal perturbations, emanating from both the autonomic nervous system and the adrenal glands. Circulating catecholamines (norepinephrine and epinephrine) and aldosterone elevations are among the salient alterations that confer significant hormonal burden on the already compromised function of the failing heart. This is why sympatholytic treatments (such as β-blockers) and renin-angiotensin system inhibitors or mineralocorticoid receptor antagonists, which block the effects of angiotensin II (AngII) and aldosterone on the failing heart, are part of the mainstay HF pharmacotherapy presently. The adrenal gland plays an important role in the modulation of cardiac neurohormonal stress because it is the source of almost all aldosterone, of all epinephrine, and of a significant amount of norepinephrine reaching the failing myocardium from the blood circulation. Synthesis and release of these hormones in the adrenals is tightly regulated by adrenal G protein-coupled receptors (GPCRs), such as adrenergic receptors and AngII receptors. In this review, we discuss important aspects of adrenal GPCR signaling and regulation, as they pertain to modulation of cardiac function in the context of chronic HF, by focusing on the 2 best studied adrenal GPCR types in that context, adrenergic receptors and AngII receptors (AT1Rs). Particular emphasis is given to findings from the past decade and a half that highlight the emerging roles of the GPCR-kinases and the β-arrestins in the adrenals, 2 protein families that regulate the signaling and functioning of GPCRs in all tissues, including the myocardium and the adrenal gland.

Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling

“…FFAR3 is robustly expressed in murine peripheral sympathetic neurons, including cardiac sympathetic nerve terminals, wherein it regulates not only cell metabolism but also neuronal activity via stimulation of NE release [ 4 ] ( Figure 5 ). Although both NE and epinephrine mediate the effects of the sympathetic nervous system on all cells and tissues, NE is the neurotransmitter synthesized, stored, and released from sympathetic neurons, whereas epinephrine is a hormone synthesized in the adrenal medulla and secreted into the systemic circulation [ 39 , 40 , 41 ]. FFAR3 knockout mice display significantly lower catecholamine synthesis, as evidenced by tyrosine hydroxylase downregulation, the enzyme that catalyzes the rate-limiting step of catecholamine biosynthesis [ 42 ], as well as lower sympathetic neuronal firing rate and heart rate [ 1 , 4 ].…”

Adrenoceptor Desensitization: Current Understanding of Mechanisms

“…Hence, therapies like β-blockers are used in the treatment of HF due to their ability to antagonize increased catecholamine stimulation, prevent HF progression and decrease mortality (Heidenreich et al, 2022;Mascolo et al, 2022). However, these drugs naturally show modest effectiveness in improving the contractile functions in many patients with HF and introduce many unwanted side effects (Borges et al, 2022;de Lucia et al, 2018;Mangmool et al, 2018).…”

Short-Chain Fatty Acid Receptors and Cardiovascular Function

“…Both FFAR2 and FFAR3 share the signature 7TM-spanning helical core of every GPCR [ 39 ]. When GPCRs are activated by ligands, the alpha subunits of heterotrimeric G proteins coupled to the receptor dissociate from the βγ subunits, further affecting intracellular signaling by activating or inhibiting the target functional proteins/enzymes (effectors) [ 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Four G protein families are known, identified after their representative subunit: Gs, Gi/o, G q/11 , and G 12/13 [ 47 , 48 ].…”