Arginine vasopressin receptor signaling and functional outcomes in heart failure

Abstract

Heart failure (HF) continues to be a highly prevalent syndrome, affecting millions of patients and costing billions of dollars in treatment per year in the United States alone. Studies in failing human heart and in transgenic HF models led to the recognition that enhanced neurohormonal signaling plays a causative role in HF progression, and the use of neurohormone receptor antagonists have proven to decrease hospitalization rates. It has also been long recognized that patients with HF have abnormal water retention, hypo-osmolality, and hyponatremia secondary to elevations in the levels of the neurohormone arginine vasopressin (AVP). AVP is released from the hypothalamus in response to changes in plasma osmolality and pressure, acting at three distinct G protein-coupled receptors: V1AR, V1BR and V2R. Persistent AVP release causes hyponatremia via renal V2R activation, a risk factor for death and hospitalization, and there is a correlation between plasma AVP levels and HF severity/survival of chronic HF patients. Because of the adverse clinical consequences associated with the development of hyponatremia, V2R antagonists were developed for the treatment of HF patients with hyponatremia, however in contrast to other neurohormone blockers they do not relay a survival benefit and may exacerbate decompensated HF requiring inotropic support. Renewed interest in the cardiac V1AR system during HF has arisen due to several recent findings: 1) mice with myocyte-selective transgenic overexpression of cardiac V1AR developed cardiomyopathy in the absence of any pathological insult, 2) cardiac V1AR expression was shown to be increased late-stage human HF, and 3) V1AR antagonism prevented cardiomyopathy development in a mouse model of HF. While cardiac V1AR expression is increased in HF, the role of V1AR signaling in various forms of cardiac injury and in distinct cardiac cell types has been controversial. Therefore this review will primarily focus on V1AR signaling as a potential therapeutic target for HF treatment.

Obestatin as a key regulator of metabolism and cardiovascular function with emerging therapeutic potential for diabetes

“…However, a clear tendency towards increased plasma obestatin levels in chronic heart failure patients is observed, which becomes significant in those with cachexia, whilst elevated circulating concentrations of both obestatin and vasopressin are associated with cardiorenal syndrome (Xin et al ., ; Shi et al ., ). Indeed, obestatin is reported to inhibit experimental angiotensin II and dehydration‐induced release of vasopressin (Samson et al ., ), which is a key regulator of physiological fluid/electrolyte balance implicated in heart failure progression (Goldsmith and Gheorghiade, ; Wasilewski et al ., ). Although current data supporting direct cardiac effects of obestatin may be limited, such actions are likely to be significant given the established structural and functional changes that occur in diabetes and which are linked to markedly increased susceptibility to hypertension and ischaemia (Bugger and Abel, ).…”

Vasopressin type 1A receptor deletion enhances cardiac contractility, β-adrenergic receptor sensitivity and acute cardiac injury-induced dysfunction

“…Consistent with these studies, cardiomyocyte-restricted ( α MHC-tTA driven) V1AR transgenic (V1ARTg) mice, with five times the expression of endogenous V1AR, developed LV hypertrophy, dilatation, reduced contractile performance and fetal gene reprogramming with progressive aging [7]. In addition, we reported that cardiac V1AR expression is increased 2-fold in human HF [6], as well as in mouse [8] and dog [5] models of HF, and that chronic V1AR inhibition during transaortic constriction (TAC) restored V1AR expression and cardiac function in mice [8]. …”

Sustained phospholipase C stimulation of H9c2 cardiomyoblasts by vasopressin induces an increase in CDP-diacylglycerol synthase 1 (CDS1) through protein kinase C and cFos

“…Several agonists including norepinephrine, angiotensin II and vasopressin (VP) acting on Gq-protein coupled receptors induce hypertrophy of cardiac myocytes [ [1] , [2] , [3] , [4] , [5] ]. Gq-protein coupled receptors activate phospholipase C (PLC) resulting in the generation of the soluble second messenger, inositol (1,4,5) trisphosphate (IP 3 ) and the membrane-bound diacylglycerol (DG).…”