ABSTRACT
The mineralocorticoid aldosterone is produced in the adrenal zona glomerulosa (ZG) under the control of the renin-angiotensin II (AngII) system. Primary aldosteronism (PA) results from renin-independent production of aldosterone and is a common cause of hypertension. PA is caused by dysregulated localization of the enzyme aldosterone synthase (Cyp11b2), which is normally restricted to the ZG. Cyp11b2 transcription and aldosterone production are predominantly regulated by AngII activation of the Gq signaling pathway. Here, we report the generation of transgenic mice with Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) specifically in the adrenal cortex. We show that adrenal-wide ligand activation of Gq DREADD receptors triggered disorganization of adrenal functional zonation, with induction of Cyp11b2 in glucocorticoid-producing zona fasciculata cells. This result was consistent with increased renin-independent aldosterone production and hypertension. All parameters were reversible following termination of DREADD-mediated Gq signaling. These findings demonstrate that Gq signaling is sufficient for adrenocortical aldosterone production and implicate this pathway in the determination of zone-specific steroid production within the adrenal cortex. This transgenic mouse also provides an inducible and reversible model of hyperaldosteronism to investigate PA therapeutics and the mechanisms leading to the damaging effects of aldosterone on the cardiovascular system.
Subject(s)
Adrenal Cortex/physiology , GTP-Binding Protein alpha Subunits, Gq-G11/physiology , Hyperaldosteronism/etiology , Zona Glomerulosa/physiology , Animals , Clozapine/analogs & derivatives , Clozapine/pharmacology , Cytochrome P-450 CYP11B2/physiology , Designer Drugs/pharmacology , Female , Hyperaldosteronism/drug therapy , Hypertension/etiology , Mice , Mice, Transgenic , Receptor, Muscarinic M3/physiology , Signal Transduction/physiologyABSTRACT
Apoptosis, a form of programmed cell death (PCD), plays an important role in the initiation and progression of a number of cardiovascular disease, such as heart failure, myocardial infarction, and atherosclerosis. One of the most prominent characteristics of apoptosis is the externalisation of phosphatidylserine (PS), a plasma cell membrane phospholipid, which in healthy cells only is present on the inner leaflet of the plasma cell membrane. Annexin A5, a 35 kD plasma protein, has strong affinity for PS in the nano-molar range. Through the coupling of Annexin A5 to contrast agents, visualization of apoptotic cell death in vivo in animal models and in patients has become feasible. These imaging studies have provided novel insight into the extent and kinetics of apoptosis in cardiovascular disease. Furthermore, Annexin A5 imaging has proven to be a suitable imaging biomarker for the evaluation of cell death modifying compounds and plaque stabilizing strategies. Recent insight in PS biology has shown that PS externalisation not only occurs in apoptosis, but is also observed in activated macrophages and stressed cells. In addition, it has been shown that Annexin A5 not only binds to exteriorized PS, but is also internalized through an Annexin A5 specific mechanism. These latter findings indicate that Annexin A5 imaging is not exclusively valuable for apoptosis detection, but can also be used to visualize inflammation and cell stress. This will open novel opportunities for imaging and drug delivery strategies. In this review we will discuss the introduction of Annexin A5 in preclinical and clinical imaging studies and provide an outlook on novel opportunities of Annexin A5 based targeting of PS.
