Description: Background— Enhanced arginine vasopressin levels are associated with increased mortality during end-stage human heart failure, and cardiac arginine vasopressin type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulates βAR responsiveness and in doing so contributes to development of heart failure. Methods and Results— Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca 2+ mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein–independent/G protein receptor kinase–dependent manner. Conclusions— This newly discovered relationship between cardiac V1AR and βAR may be informative for the treatment of patients with acute decompensated heart failure and elevated arginine vasopressin.

Description: Objective— Thymocyte apoptosis is a major event in sepsis; however, how this process is regulated remains poorly understood. Approach and Results— Septic stress induces glucocorticoids production which triggers thymocyte apoptosis. Here, we used scavenger receptor BI (SR-BI)–null mice, which are completely deficient in inducible glucocorticoids in sepsis, to investigate the regulation of thymocyte apoptosis in sepsis. Cecal ligation and puncture induced profound thymocyte apoptosis in SR-BI +/+ mice, but no thymocyte apoptosis in SR-BI –/– mice because of lack of inducible glucocorticoids. Unexpectedly, supplementation of glucocorticoids only partly restored thymocyte apoptosis in SR-BI –/– mice. We demonstrated that high-density lipoprotein (HDL) is a critical modulator for thymocyte apoptosis. SR-BI +/+ HDL significantly enhanced glucocorticoid-induced thymocyte apoptosis, but SR-BI –/– HDL had no such activity. Further study revealed that SR-BI +/+ HDL modulates glucocorticoid-induced thymocyte apoptosis via promoting glucocorticoid receptor translocation, but SR-BI –/– HDL loses such regulatory activity. To understand why SR-BI –/– HDL loses its regulatory activity, we analyzed HDL cholesterol contents. There was 3-fold enrichment of unesterified cholesterol in SR-BI –/– HDL compared with SR-BI +/+ HDL. Normalization of unesterified cholesterol in SR-BI –/– HDL by probucol administration or lecithin cholesteryl acyltransferase expression restored glucocorticoid-induced thymocyte apoptosis, and incorporating unesterified cholesterol into SR-BI +/+ HDL rendered SR-BI +/+ HDL dysfunctional. Using lckCre-GR fl/fl mice in which thymocytes lack cecal ligation and puncture–induced thymocyte apoptosis, we showed that lckCre-GR fl/fl mice were significantly more susceptible to cecal ligation and puncture–induced septic death than GR fl/fl control mice, suggesting that glucocorticoid-induced thymocyte apoptosis is required for protection against sepsis. Conclusions— The findings in this study reveal a novel regulatory mechanism of thymocyte apoptosis in sepsis by SR-BI and HDL.