Chang-Xi Bai

BACKGROUND: Female sex is an independent risk factor for torsade de pointes in long-QT syndrome. In women, QT interval and torsade de pointes risk fluctuate dynamically during the menstrual cycle and pregnancy. Accumulating clinical evidence suggests a role for progesterone; however, the effect of progesterone on cardiac repolarization remains undetermined. METHODS AND RESULTS: We investigated the effects of progesterone on action potential duration and membrane currents in isolated guinea pig ventricular myocytes. Progesterone rapidly shortened action potential duration, which was attributable mainly to enhancement of the slow delayed rectifier K+ current (I(Ks)) under basal conditions and inhibition of L-type Ca2+ currents (I(Ca,L)) under cAMP-stimulated conditions. The effects of progesterone were mediated by nitric oxide released via nongenomic activation of endothelial nitric oxide synthase; this signal transduction likely takes place in the caveolae because sucrose density gradient fractionation experiments showed colocalization of the progesterone receptor c-Src, phosphoinositide 3-kinase, Akt, and endothelial nitric oxide synthase with KCNQ1, KCNE1, and Ca(V)1.2 in the caveolae fraction. We used computational single-cell and coupled-tissue action potential models incorporating the effects of progesterone on I(Ks) and I(Ca,L); the model reproduces the fluctuations of cardiac repolarization during the menstrual cycle observed in women and predicts the protective effects of progesterone against rhythm disturbances in congenital and drug-induced long-QT syndrome. CONCLUSIONS: Our data show that progesterone modulates cardiac repolarization by nitric oxide produced via a nongenomic pathway. A combination of experimental and computational analyses of progesterone effects provides a framework to understand complex fluctuations of QT interval and torsade de pointes risks in various hormonal states in women.

Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of kidney failure, is caused by mutations in either PKD1 (85%) or PKD2 (15%). The PKD2 protein, polycystin-2 (PC2 or TRPP2), is a member of the transient receptor potential (TRP) superfamily and functions as a non-selective calcium channel. PC2 has been found to form oligomers in native tissues suggesting that it may form functional homo- or heterotetramers with other subunits, similar to other TRP channels. Our experiments unexpectedly revealed that PC2 mutant proteins lacking the known C-terminal dimerization domain were still able to form oligomers and co-immunoprecipitate full-length PC2, implying the possible existence of a proximal dimerization domain. Using yeast two-hybrid and biochemical assays, we have mapped an alternative dimerization domain to the N terminus of PC2 (NT2-1-223, L224X). Functional characterization of this domain demonstrated that it was sufficient to induce cyst formation in zebrafish embryos and inhibit PC2 surface currents in mIMCD3 cells probably by a dominant-negative mechanism. In summary, we propose a model for PC2 assembly as a functional tetramer which depends on both C- and N-terminal dimerization domains. These results have significant implications for our understanding of PC2 function and disease pathogenesis in ADPKD and provide a new strategy for studying PC2 function.

This study examined the different effects of high-fat and capsicum diets on the digestive organs of guinea pigs. Hartley guinea pigs (n = 24) were divided into the high-fat diet (HFD), capsicum diet (CD), and control (C) groups. Guinea pigs in the C, HFD, and CD groups received maintenance feed, high-fat, and capsicum diets, respectively. After 12 weeks of modelling, serum samples were collected for biochemical analysis. Enzyme-linked immunosorbent assay was used to quantify interleukin-1β, interleukin-6, and tumour necrosis factor-α, while haematoxylin-eosin staining was used to observe morphological changes. Blood lipid levels and inflammatory markers in the serum of guinea pigs in HFD and CD groups were significantly elevated than those in the serum of guinea pigs in the C group (P < 0.01). Inflammation and blood lipid disorders were more severe among guinea pigs in the HFD group than among those in the CD and C groups (P < 0.001). Pathological examinations revealed that high-fat and capsicum diets induce damage to the liver, stomach, gallbladder, and colon. Specifically, high-fat diets exhibited more significant effects. High-fat or capsicum diet consumption can damage the digestive organs, causing abnormal lipid metabolism; however, high-fat diets exhibit more significant effects on the digestive organs.