Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through b-adrenoceptors
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ABSTRACT:
PROVIDER: PRJNA783279 | ENA |
REPOSITORIES: ENA
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Project description:Baroreflex control of cardiac contraction (positive inotropy) through sympathetic nerve activation is important to maintain cardiocirculatory homeostasis. Transient receptor potential canonical subfamily (TRPC) channels are responsible for alfa1-adrenoceptor (alfa1AR)-stimulated cation entry and their upregulation is reportedly associated with pathological cardiac remodeling, but whether TRPC channels participate in physiological pump functions remains unclear. Here, we demonstrate that TRPC6-specific Zn2+ influx potentiates alfa-adrenoceptor (alfaAR)-stimulated positive inotropy in rodent cardiomyocytes. Deletion of the trpc6 gene impairs sympathetic nerve-activated positive inotropy, but not chronotropy in mice. TRPC6-mediated Zn2+ influx boosts alfa1AR-stimulatedalfaAR/Gs-dependent signaling in rat cardiomyocytes by inhibiting alfa-arrestin-mediated alfaAR internalization. Replacing two TRPC6-specific amino acids in the pore region with those of TRPC3 diminishes the alfa1AR-stimulated Zn2+ influx and positive inotropic response. Pharmacological enhancement of TRPC6-mediated Zn2+ influx prevents the progression of heart failure in dilated cardiomyopathy mice. Our data provide evidence that TRPC6-mediated Zn2+ influx with α1AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.
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Project description:To investigate the mechanism of TRPC1 or TRPC6 on the regulation of endotoxemic cardiac dysfunction, we established Trpc1-/- and Trpc6-/- mice. LPS-challenged endotoxemic mouse model was built, and the gene expression profile was analyzed using data obtained from RNA-seq of WT, LPS-challenged WT, LPS-challenged Trpc1-/-, and LPS-challenged Trpc6-/- mice hearts.
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Project description:Inhibition of transient receptor potential canonical 6 channels (TRPC6) alleviates tubular injury and renal fibrosis induced by unilateral ureteral obstruction (UUO).However, the exact renoprotective mechanisms are unknown. In this study, we utilized single-cell RNA sequencing (scRNA-Seq) to define the cellular and transcriptional landscape associated with renoprotection through in vivo TRPC6 inhibition, specifically using SH045 (larixyl N-methylcarbamate), in the UUO model.
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Project description:Zinc (Zn2+) is an important trace metal ion that has been shown to regulate the expression of several (virulence) genes in streptococci. Previously, we analyzed the genome-wide response of S. pneumoniae to Zn2+-stress. In this work, we have performed a transcriptomic analysis to identify genes that are differentially expressed under intracellular Zn2+-limitation. This revealed a number of genes that are highly upregulated in the absence of extracellular Zn2+, amongst which the genes belonging to the regulon of the Zn2+-responsive repressor AdcR, like adcBCA, encoding a Zn2+-dependent ABC-uptake system, adcAII, encoding a Zn2+-binding lipoprotein, and also virulence genes belonging to the Pht family (phtA, phtB, phtD and phtE). Using transcriptome analysis, lacZ-reporter studies, in vitro DNA binding experiments, and in silico operator predictions, we show that AdcR directly represses the promoters of adcRCBA, adcAII-phtD, phtA, phtB and phtE in the presence of Zn2+. AdcR can also function as an activator, since in the presence of Zn2+ it directly induces expression of adh that encodes a Zn2+-containing alcohol dehydrogenase. In conclusion, the genome-wide transcriptional response of S. pneumoniae to Zn2+-limitation was established, which is mainly mediated via direct regulation by the Zn2+-dependent regulator AdcR. Two condition design comparison of Wild-type strain including a dye swap Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE29234: adcR mutant vs wild type D39 GSE29235: Low Zn vs high Zn in CDM
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