Controlled and Cardiac-Restricted Overexpression of the Arginine Vasopressin V1A Receptor Causes Reversible Left Ventricular Dysfunction Through G alpha(q)-Mediated Cell Signaling
ABSTRACT [Arg8]-vasopressin (AVP) activates 3 G-protein-coupled receptors: V1A, V2, and V1B. The AVP-V1A receptor is the primary AVP receptor in the heart; however, its role in cardiac homeostasis is controversial. To better understand AVP-mediated signaling in the heart, we created a transgenic mouse with controlled overexpression of the V1A receptor.
The V1A receptor transgene was placed under the control of the tetracycline-regulated, cardiac-specific α-myosin heavy chain promoter (V1A-TG). V1A-TG mice had a normal cardiac function phenotype at 10 weeks of age; however, by 24 weeks of age, tetracycline-transactivating factor/V1A-TG mouse hearts had reduced cardiac function, cardiac hypertrophy, and dilatation of the ventricular cavity. Contractile dysfunction was also observed in isolated adult cardiac myocytes. When V1A receptor transgene was induced to be expressed in adult mice (V1A-TG(Ind)), left ventricular dysfunction and dilatation were also seen, albeit at a later time point. Because the V1A receptor mediates cell signaling through Gα(q) protein, we blocked Gα(q) signaling by crossing tetracycline-transactivating factor/V1A mice with transgenic mice that expressed a small inhibitory peptide against Gα(q). Gα(q) blockade abrogated the development of the heart failure phenotype in tetracycline-transactivating factor/V1A-TG mice. The heart failure phenotype could be reversed by administration of doxycycline.
Our results demonstrate a role for V1A-mediated signaling in the development of heart failure and support a role for V1A blockade in the treatment of patients with elevated levels of vasopressin.
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ABSTRACT: Hyponatremia is a well known predictor of short-term outcomes in heart failure (HF); however, its impact on long-term survival in HF patients with systolic dysfunction is not well established. Using the Duke Databank for Cardiovascular Diseases, we identified 1,045 patients with HF and systolic dysfunction undergoing cardiac catheterization from January 2000 through December 2008. The effect of hyponatremia as independent predictor of all-cause death and cardiovascular death/rehospitalization was examined using a multivariable Cox proportional regression model. Hyponatremia was present in 107/1,045 patients (10.2%). Hyponatremic patients were older, more likely to be anemic, with higher heart rate and levels of blood urea nitrogen, lower blood pressure, and more severe HF. Using an unadjusted analysis, hyponatremia was associated with higher risk of all-cause death (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.44-2.49; P < .0001) and of cardiovascular death/rehospitalization (HR 1.40, 95% CI 1.11-1.77; P = .005) at 4.5 years. When entered into a multivariable Cox model, hyponatremia remained significant for all-cause death (HR 1.42, 95% CI 1.07-1.88) and for cardiovascular death/rehospitalization (HR 1.45, 95% CI 1.14-1.86). Hyponatremia is relatively common in HF patients with LV dysfunction and is independently associated with increased risk of all-cause mortality and cardiovascular mortality/rehospitalization.Journal of cardiac failure 01/2012; 18(1):74-81. DOI:10.1016/j.cardfail.2011.09.005 · 3.07 Impact Factor
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ABSTRACT: Although recent clinical trials have demonstrated the efficacy of the oral vasopressin (AVP) type 2 receptor (V2R) antagonist tolvaptan, its long-term effects on the myocardium and kidney in heart failure (HF) are not clear. We examined the chronic effects of tolvaptan administration on both the myocardium and kidney in a rat hypertensive HF model. Not only circulating AVP level but also myocardial AVP and V1a receptor (V1aR) expressions, renal V1aR, and V2R expressions were significantly upregulated during the transition to HF. The animals were chronically treated with low-dose or high-dose (HD) tolvaptan or vehicle from the left ventricular (LV) hypertrophic stage. Chronic tolvaptan treatment persistently increased urine volume but did not affect blood pressure. In the HD group, the animal survival significantly improved (log-rank test, P<0.01). At the HF stage, the progression of LV dysfunction was prevented and lung congestion was suppressed. Activation of atrial natriuretic peptide, endothelin-1, AVP, and V1aR mRNA levels were significantly suppressed in the LV myocardium. Meanwhile, renal histopathologic damage was ameliorated and renal function was improved in the HD group at the HF stage. Concomitantly, not only activation of aquaporin-2 but also those of V2R, V1aR, renin, and endothelin-1 in the kidney were significantly suppressed (all P<0.05). These results indicate that chronic tolvaptan treatment has beneficial effects by preventing not only the progression of LV dysfunction but also that of renal injury in hypertensive rats with HF. The underlying mechanism may be related to the suppression of myocardial and renal neurohumoral activation.Circulation Heart Failure 05/2012; 5(4):484-92. DOI:10.1161/CIRCHEARTFAILURE.111.965392 · 5.95 Impact Factor
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ABSTRACT: An increasing body of evidence reported in the literature indicates a possible role for post-traumatic stress disorder (PTSD) as a cause for cardiovascular disease (CVD). However, mechanistic evidence on the progression of adverse cardiac outcomes in PTSD is lacking. In this review, we examine the potential paths by which CVD could occur in those with PTSD. Dysregulation of the hypothalamic-pituitary-adrenal axis and autonomic nervous dysfunction are commonly observed in PTSD, which in turn lead to a variety of physiological changes potentially damaging to the heart. Increased inflammation, dysfunction of the vascular endothelium, hypercoagulability, and cardiac hyperreactivity all have been noted in patients with PTSD. Altered neurochemistry, most notably increased arginine vasopressin, as well as an increased prevalence of the metabolic syndrome, may also contribute to adverse cardiac outcomes. While the association between PTSD and physical disease is often complicated by health risk behaviors or comorbid psychiatric conditions, the evidence for a link between PTSD and CVD is substantial. In our examination, we attempt to identify potential cardiac biomarkers that may be useful in detecting increased cardiac risk in PTSD patients. As research in this area is exceedingly limited, we hope to inspire further research, as there is great potential value in identifying prognostically useful cardiac biomarkers so as to predict and prevent the onset of CVD in PTSD patients.Cardiology in review 06/2012; 21(1). DOI:10.1097/CRD.0b013e318265343b · 3.24 Impact Factor