Adenylyl cyclase type 5 in cardiac disease, metabolism, and aging

Abstract

G protein-coupled receptor/adenylyl cyclase (AC)/cAMP signaling is crucial for all cellular responses to physiological and pathophysiological stimuli. There are nine isoforms of membrane-bound AC, with type 5 being one of the two major isoforms in the heart. Since the role of AC in the heart in regulating cAMP and acute changes in inotropic and chronotropic state are well known, this review will address our current understanding of the distinct regulatory role of the AC5 isoform in response to chronic stress. Transgenic overexpression of AC5 in cardiomyocytes of the heart (AC5-Tg) improves baseline cardiac function but impairs the ability of the heart to withstand stress. For example, chronic catecholamine stimulation induces cardiomyopathy, which is more severe in AC5-Tg mice, mediated through the AC5/sirtuin 1/forkhead box O3a pathway. Conversely, disrupting AC5, i.e., AC5 knockout, protects the heart from chronic catecholamine cardiomyopathy as well as the cardiomyopathies resulting from chronic pressure overload or aging. Moreover, AC5 knockout results in a 30% increase in a healthy life span, resembling the most widely studied model of longevity, i.e., calorie restriction. These two models of longevity share similar gene regulation in the heart, muscle, liver, and brain in that they are both protected against diabetes, obesity, and diabetic and aging cardiomyopathy. A pharmacological inhibitor of AC5 also provides protection against cardiac stress, diabetes, and obesity. Thus AC5 inhibition has novel, potential therapeutic applicability to several diseases not only in the heart but also in aging, diabetes, and obesity.

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…Based on experiments with AC5 knockout mice (see section II. E.3.a), it has been proposed that selective AC5 inhibition may be beneficial in the treatment of heart failure and other age-related diseases (Vatner et al, 2013;Bravo et al, 2016). However, AC5 is broadly expressed in many organs, including kidney (Erdorf and Seifert, 2011) and brain (Kim and Han, 2009), so that substantial organ toxicity could emerge as a result of global AC5 inhibition (Table 3).…”

“…It is particularly important to confirm that the AC inhibitor used actually prevents a GPCR-or FSKmediated cAMP increase (Brunskole Hummel et al, 2013). Because vidarabine constitutes an FDAapproved antiviral drug, the clinical use of this compound for AC5 inhibition has been proposed (Vatner et al, 2013;Bravo et al, 2016). Unfortunately, vidarabine possesses a high potential for toxic effects so that systemic clinical use would potentially be dangerous (Seifert, 2014(Seifert, , 2016.…”

A Type 2 Diabetes–Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus

“…ADCY5 encodes adenylate cyclase 5, which catalyzes generation of cyclic AMP (cAMP) from ATP (16). cAMP, ATP, and calcium (Ca 2+ ) regulate insulin secretion in the pancreatic islet β-cell (17).…”

Structure/Activity Relationships of (M)ANT- and TNP-Nucleotides for Inhibition of Rat Soluble Guanylyl Cyclase α1β1

“…Specifically, it has been suggested that selective AC5 inhibitors may be valuable drugs for the treatment of heart failure (Vatner et al, 2013). However, it is difficult to develop highly selective AC5 inhibitors (Braeunig et al, 2013;Brand et al, 2013;Seifert, 2014), and in the context of heart failure, additional inhibition of sGC would be detrimental for cardiovascular function (Schermuly et al, 2011;Gheorghiade et al, 2013).…”