Stabilization of RyR2 maintains right ventricular function, reduces the development of ventricular arrhythmias, and improves prognosis in pulmonary hypertension

Tanaka, Shinji; Yamamoto, Takakazu; Mikawa, Mei; Nawata, Jun; Fujii, Shohei; Nakamura, Yoshihide; Kato, Takayoshi; Fukuda, Masakazu; Suetomi, Takeshi; Uchinoumi, Hitoshi; Oda, Tatsuya; Okuda, Shinichi; Okamura, Takayuki; Kobayashi, Shigeki; Yano, Masafumi

doi:10.1016/j.hrthm.2022.02.003

Cited by 11 publications

(6 citation statements)

References 33 publications

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“…However, the exact mechanism by which VA arises in PAH-induced RHF is poorly understood. Evidence shows that Ca 2+ handling abnormalities play a pivotal role in ventricular arrhythmogenesis in hearts with PAH-induced RHF [ 6 , 7 ]. In this regard, mitigation of impaired Ca 2+ handling could be a promising therapeutic approach for the prevention of VA after PAH-induced RHF.…”

Section: Introductionmentioning

confidence: 99%

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling

Liu

Shu

et al. 2022

Cardiovasc Diabetol

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Background Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF. Methods Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM. Results High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy. Conclusion DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

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Section: Introductionmentioning

confidence: 99%

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling

Liu

Shu

et al. 2022

Cardiovasc Diabetol

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“…Nineteen studies were selected after applying the exclusion and inclusion criteria (Figure 1) [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. They were published between 2009 and 2022, providing data for twenty drugs and two combinations of two drugs, with a great variety of mechanisms of action (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Approaches in Pulmonary Arterial Hypertension with Beneficial Effects on Right Ventricular Function—Preclinical Studies

Balsa,

Adão,

Brás-Silva

2023

IJMS

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Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many mice/rat models are used for research in PAH, but results fail to translate to clinical trials. This study reviews studies that test interventions on pulmonary artery banding (PAB), a model of isolated RV disfunction, and PH models. Multiple tested drugs both improved pulmonary vascular hemodynamics in PH models and improved RV structure and function in PAB animals. PH models and PAB animals frequently exhibited similar results (73.1% concordance). Macitentan, sildenafil, and tadalafil improved most tested pathophysiological parameters in PH models, but almost none in PAB animals. Results are frequently not consistent with other studies, possibly due to the methodology, which greatly varied. Some research groups start treating the animals immediately, and others wait up to 4 weeks from model induction. Treatment duration and choice of anaesthetic are other important differences. This review shows that many drugs currently under research for PAH have a cardioprotective effect on animals that may translate to humans. However, a uniformization of methods may increase comparability between studies and, thus, improve translation to clinical trials.

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“…[97] and CYP3A5 [98] have been shown in schizophrenia. Recent studies showed that SLC6A9 [99], FKBP1B [100], S100A12 [101], SLC6A19 [102], TXN (thioredoxin) [103], TLR9 [104], HP (haptoglobin) [105], ARG1 [106], PINK1 [107], B2M [108], C5AR1 [109], MYADM (myeloid associated differentiation marker) [110], CBS (cystathionine beta-synthase) [111], GPX1 [112], SIAH2 [113], PRDX2 [114], RDH8 [115], CYP11B2 [116], RARRES2 [117], NOX1 [118], IL33 [119], OTC (ornithine transcarbamylase) [120], CYP1A1 [121], NFATC4 [122], TSLP (thymic stromal lymphopoietin) [123], WNT4 [124], MGP (matrix Gla protein) [125], FGFBP1 [126], GHR (growth hormone receptor) [127], ERBB3 [128], GFAP (glial fibrillary acidic protein) [129], CCDC40 [130], CACNB2 [131], CD34 [132], NOTCH3 [133], TERT (telomerase reverse transcriptase) [134], GNB3 [135], TP73 [136], RYR2 [137], ENPEP (glutamyl aminopeptidase) [138], SCN7A [139], WNK4 [140], SFRP5 [141], GDF15 [142], CAV1 [143], KCNA5 [144], FOXC1 [145], ASIC1 [146], VASH2 [147], CXCL8 [148], PAPPA2…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Biological Pathways in Bipolar Disorder by Bioinformatics and Next Generation Sequencing Data Analysis

Vastrad¹,

Vastrad²

2022

Preprint

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Bipolar disorder (BD), also known as psychiatric disorder, affects millions of people all over the world. The aim of this investigation was to screen and verify hub genes involved in BD as well as to explore potential molecular mechanisms. The next generation sequencing (NGS) dataset GSE124326 was downloaded from the Gene Expression Omnibus (GEO) database, which contained 480 samples, including 240 BD and 240 normal controls. Differentially expressed genes (DEGs) were filtered and subjected to gene ontology (GO) and pathway enrichment analyses. A protein–protein interaction (PPI) network and module analysis were used to identify hub genes. The miRNA-hub gene regulatory network and TF-hub gene regulatory network were also constructed. Receiver operating characteristic curve (ROC) analysis was used to validate hub genes. In this work, 957 DEGs, including 477 up regulated and 480 down regulated, were obtained from NGS data. The GO and pathway enrichment analyses of the DEGs showed that the up regulated genes were enriched in the neutrophil degranulation, immune system, transport, cytoplasm and enzyme regulator activity, and the down regulated genes were enriched in extracellular matrix organization, diseases of metabolism, multicellular organismal process, cell periphery and metal ion binding. Finally, through analyzing the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network, we screened hub genes UBB, UBE2D1, TUBA1A, RPL11, RPS24, NOTCH3, CAV1, CNBD2, CCNA1 and MYH11 by the Cytoscape software. The current investigation illustrates a characteristic NGS data in BD, which might contribute to the interpretation of the progression of BD and provide novel biomarkers and therapeutic targets for BD.

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Stabilization of RyR2 maintains right ventricular function, reduces the development of ventricular arrhythmias, and improves prognosis in pulmonary hypertension

Cited by 11 publications

References 33 publications

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling

Therapeutic Approaches in Pulmonary Arterial Hypertension with Beneficial Effects on Right Ventricular Function—Preclinical Studies

Identification of Key Genes and Biological Pathways in Bipolar Disorder by Bioinformatics and Next Generation Sequencing Data Analysis

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