Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

Abstract

The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)—particularly βARs—play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.

Mitochondrial microRNAs Are Dysregulated in Patients with Fabry Disease

“…The mechanisms underlying mitomiRs biogenesis and action sites are still poorly understood, however they are a fascinating class of miRNAs which could allow to track the mitochondrial status and health in pathological conditions (Latronico and Condorelli, 2012). Indeed, differentially expressed mitomiRs have been observed in heart failure (Pinti et al, 2017;Wang et al, 2017), where mitochondrial dysfunction is evident (Santulli et al, 2015;Sties et al, 2018;Del Campo et al, 2021;Guitart-Mampel et al, 2021;Morciano et al, 2021;Yang et al, 2021;Schwemmlein et al, 2022). Despite their potential power in mirroring systemic mitochondrial homeostasis, the assessment of mitomiRs in FD has never been contemplated.…”

Plasma Biomarker Profiling in Heart Failure Patients with Preserved Ejection Fraction before and after Spironolactone Treatment: Results from the Aldo-DHF Trial

“…Spironolactone is known to reduce morbidity and mortality in patients with severe HFrEF [28]. It exerts its beneficial effects through mineralocorticoid receptor (MR) blockade and may thereby attenuate maladaptive downstream effects through aldosterone-mediated MR activation, e.g., increases in reactive oxygen species, inflammation, fibrosis, mito-chondrial dysfunction and adrenergic receptor modulation [29,30]. In the Aldo-DHF trial, distinct beneficial effects through spironolactone treatment in HFpEF patients were demonstrated including an improvement of diastolic function and neuroendocrine activation, as well as a reduction of adverse cardiac remodelling [5].…”

Role and Mechanism of the Renin-Angiotensin-Aldosterone System in the Onset and Development of Cardiorenal Syndrome

“…Excessive activation of RAAS causes abnormal production of Ang II and aldosterone in the blood circulation, which can activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the heart, promoting ROS generation and leading to oxidative stress [ 11 , 24 , 33 ]. Oxidative stress promotes the development of arteriosclerosis and cardiac fibrosis, accelerating the occurrence and development of CRS [ 34 , 35 ].…”

“…These effects can lead to mitochondrial and adrenergic receptor dysfunction and coronary vasoconstriction which can lead to HF. Moreover, aldosterone stimulates epidermal growth factor receptor activation through activating MR, which regulates the RAAS and ultimately modulates cardiac physiology [ 24 ].…”