Adrenal βarrestin1 targeting for tobacco–associated cardiac dysfunction treatment: Aldosterone production as the mechanistic link

Abstract

Tobacco kills 6 million people annually and its global health costs are continuously rising. The main addictive component of every tobacco product is nicotine. Among the mechanisms by which nicotine, and its major metabolite, cotinine, contribute to heart disease is the renin‐angiotensin‐aldosterone system (RAAS) activation. This increases aldosterone production from the adrenals and circulating aldosterone levels. Aldosterone is a mineralocorticoid hormone with various direct harmful effects on the myocardium, including increased reactive oxygen species (ROS) generation, which contributes significantly to cardiac mitochondrial dysfunction and cardiac aging. Aldosterone is produced in the adrenocortical zona glomerulosa (AZG) cells in response to angiotensin II (AngII), activating its type 1 receptor (AT 1 R). The AT 1 R is a G protein‐coupled receptor (GPCR) that leads to aldosterone biosynthesis and secretion, via signaling from both G q/11 proteins and the GPCR adapter protein βarrestin1, in AZG cells. Adrenal βarrestin1 is essential for AngII–dependent adrenal aldosterone production, which aggravates heart disease. Since adrenal βarrestin1 is essential for raising circulating aldosterone in the body and tobacco compounds are also known to elevate aldosterone levels in smokers, accelerating heart disease progression, our central hypothesis is that nicotine and cotinine increase aldosterone levels to induce cardiac injury by stimulating adrenal βarrestin1. In the present review, we provide an overview of the current literature of the physiology and pharmacology of adrenal aldosterone production regulation, of the effects of tobacco on this process and, finally, of the effects of tobacco and aldosterone on cardiac structure and function, with a particular focus on cardiac mitochondrial function. We conclude our literature account with a brief experimental outline, as well as with some therapeutic perspectives of our pharmacological hypothesis, that is that adrenal βarrestin1 is a novel molecular target for preventing tobacco–induced hyperaldosteronism, thereby also ameliorating tobacco–related heart disease development.

Nicotine Diminishes Alpha2-Adrenergic Receptor-Dependent Protection Against Oxidative Stress in H9c2 Cardiomyocytes

“…Most likely, however, it occurs at the transcriptional level, similarly to the adrenal βarrestin1 upregulation that nicotine also induces to elevate aldosterone production and cause hyperaldosteronism. 28,29 Our present study further expands this list with the addition of diminishing the anti-oxidative protection of adrenergic agonists in the heart courtesy of α 2 AR dysfunction. Importantly, α 2 ARs are downregulated in human HF, 10 contributing to the enhanced sympathetic nervous system activity that accompanies and aggravates human chronic HF.…”

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

“…b-arrestin1 directly interacts with the Ca 2+ channel TRPC3 (short transient receptor potential channel-3) at the plasma membrane eliciting CA secretion. 80 However, the main physiological role of the AT 1 R in the adrenal gland is mapped in the adrenal cortex, where it induces synthesis and secretion of aldosterone [81][82][83][84] (Fig. 1).…”

An integral perspective of canonical cigarette and e-cigarette-related cardiovascular toxicity based on the adverse outcome pathway framework

“…Aldosterone is a mineralocorticoid hormone that induced direct adverse effects on cardiomyocytes, especially including the excessive generation of ROS. Cardiac dysfunction induced by aldosterone has been attributed primarily to mitochondrial damage caused by elevated ROS levels, such as oxidative damage to mitochondrial DNA [98] . Aldosterone and subsequent ROS elevation have also been proved to be associated with systolic and diastolic dysfunction, and ROS overproduction could induce deterioration of systolic and diastolic function through disturbance of cardiac mechanics [99] .…”