Rattus norvegicus
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ABSTRACT:
PROVIDER: PRJNA230412 | ENA |
REPOSITORIES: ENA
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Project description:Rats with adenine-induced chronic renal failure (A-CRF) develop a reduction in the rate of relaxation of the thoracic aorta. The primary aim of this study was to elucidate the mechanisms underlying this abnormality. Male Sprague-Dawley rats received either chow containing adenine or were pair-fed with normal chow (controls). After 8-14 weeks arterial functions were analyzed ex vivo using wire myography and the thoracic aorta was analyzed by DNA microarray. Plasma creatinine levels were elevated ~8-fold in A-CRF rats. The rate of vascular relaxation following wash-out of KCl was reduced in A-CRF rats vs. controls in the thoracic aorta (P<0.01), abdominal aorta (P<0.05), and common carotid artery (P<0.05), but not in the common femoral artery. Endothelial denudation exaggerated the impairment in relaxation of thoracic aortas. Relaxation rates of thoracic aortas increased (P<0.01), but were not normalized, in response to wash-out of KCl with Ca2+-free buffer. Microarray and qRT-PCR analyses revealed altered gene expression levels for a number of genes involved in vascular smooth muscle cell excitation-contraction coupling in aortas of A-CRF rats. In conclusion, rats with A-CRF show a marked reduction in the rate of relaxation of larger conduit arteries localized proximal to the common femoral artery. This abnormality may be caused by reduced cytosolic Ca2+ clearance in vascular smooth muscle cells secondary to dysregulation of genes involved in excitation-contraction coupling.
2016-07-21 | GSE52897 | GEO
Project description:Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this novel role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.
2021-03-09 | GSE168487 | GEO
Project description:Background: Niemann-Pick disease type A (NPDA), a disease caused by mutations in acid sphingomyelinase (ASM), involves severe neurodegeneration and early death. Intracellular lipid accumulation and plasma membrane alterations are implicated in the pathology. ASM is also linked to the mechanism of plasma membrane repair, so we investigated the impact of ASM deficiency in skeletal muscle, a tissue that undergoes frequent cycles of injury and repair in vivo. Methods: Utilizing the NPDA/B mouse model ASM−/− and wild type (WT) littermates, we performed excitation- contraction coupling/Ca2+ mobilization and sarcolemma injury/repair assays with isolated flexor digitorum brevis fibers, proteomic analyses with quadriceps femoris, flexor digitorum brevis, and tibialis posterior muscle and in vivo tests of the contractile force (maximal isometric torque) of the quadriceps femoris muscle before and after eccentric contraction-induced muscle injury. Results: ASM−/− flexor digitorum brevis fibers showed impaired excitation-contraction coupling compared to WT, a defect expressed as reduced tetanic [Ca2+]i in response to electrical stimulation and early failure in sustaining [Ca2+]i during repeated tetanic contractions. When injured mechanically by needle passage, ASM−/− flexor digitorum brevis fibers showed susceptibility to injury similar to WT, but a reduced ability to reseal the sarcolemma. Proteomic analyses revealed changes in a small group of skeletal muscle proteins as a consequence of ASM deficiency, with downregulation of calsequestrin occurring in the three different muscles analyzed. In vivo, the loss in maximal isometric torque of WT quadriceps femoris was similar immediately after and 2 min after injury. The loss in ASM−/− mice immediately after injury was similar to WT, but was markedly larger at 2 min after injury. Conclusions: Skeletal muscle fibers from ASM−/− mice have an impairment in intracellular Ca2+ handling that results in reduced Ca2+ mobilization and a more rapid decline in peak Ca2+ transients during repeated contraction-relaxation cycles. Isolated fibers show reduced ability to repair damage to the sarcolemma, and this is associated with an exaggerated deficit in force during recovery from an in vivo eccentric contraction- induced muscle injury. Our findings uncover the possibility that skeletal muscle functional defects may play a role in the pathology of NPDA/B disease.
2023-06-28 | PXD019356 | Pride
Project description:In cardiomyocytes, Ca2+ influx through L-type voltage-gated calcium channels (LTCCs) following membrane depolarization regulates crucial Ca2+-dependent processes including duration and amplitude of the action potentials and excitation-contraction coupling. LTCCs are heteromultimeric proteins composed of the Cav1, Cav, Cav2 and Cav subunits. Here, using ascorbate peroxidase (APEX)-mediated proximity labeling and quantitative proteomics, we identified 61 proteins in the nano-environments of Cav2 in cardiomyocytes. These proteins are involved in diverse cellular functions such as cellular trafficking, muscular contraction, sarcomere organization and excitation-contraction coupling. Moreover, pull-down assays, co-immunoprecipitation analyses and super-resolution imaging using direct stochastic optical reconstruction microscopy (dSTORM) revealed that Cav2 interacts with the ryanodine receptor 2 (RyR2) in adult cardiomyocytes, probably coupling LTCCs and the RyR2 into a supramolecular complex at the dyads. This interaction is mediated by the Src-homology 3 domain of Cav2 and is necessary for an effective pacing frequency‐dependent increase of the Ca2+-induced Ca2+ release mechanism in cardiomyocytes.
2021-12-14 | PXD021375 | Pride
Project description:Our aim is to analyze how does the lack of each of the Ca2+ channels, involved in excitation-contraction coupling in skeletal muscle - RYR1 and Cav1.1, affect gene expression in embryonic mouse limb skeletal muscle during secondary myogenesis. We extracted total RNA from the limb skeletal muscle of WT, heterozygous RYR1-/+ and Cav1.1+/-, and homozygous RYR1-/- and Cav1.1-/- mutants from 3 litters (n = 3 for each group) at days E14.5 and E18.5 and subjected it to microarray analyses.
2017-11-24 | E-MTAB-5755 | biostudies-arrayexpress
Project description:Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in adult-onset dilated cardiomyopathy (DCM) characterized by sterile inflammation and cardiac fibrosis that progressed to heart failure and middle-aged death. Failing hearts from cardiomyocyte-restricted knockout mice displayed a general decline in mitochondrial gene expression and oxidative phosphorylation (OXPHOS) activity. Pre-DCM, we observed no defects in mitochondrial morphology, content, gene expression, OXPHOS assembly nor phosphorylation dependent respiration. However, knockout cardiac mitochondria displayed reduced membrane potential and increased non-phosphorylation dependent respiration, which could be rescued by pharmacological inhibition of the adenine nucleotide translocase ANT. Primary cardiomyocytes from pre-symptomatic knockout mice exhibited normal excitation-contraction coupling but increased sensitivity to programmed cell death (PCD), which was accompanied by an opening of the mitochondrial permeability transition pore (mPTP). Intriguingly, mouse embryonic fibroblasts deleted for Mtfp1 recapitulated PCD sensitivity and mPTP opening, both of which could be rescued by pharmacological or genetic inhibition of the mPTP regulator Cyclophilin D. Collectively, our data demonstrate that contrary to previous in vitro studies, the loss of the MTFP1 promotes mitochondrial uncoupling and increases cell death sensitivity, causally mediating pathogenic cardiac remodeling
2022-10-06 | PXD028516 | Pride
Project description:Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in adult-onset dilated cardiomyopathy (DCM) characterized by sterile inflammation and cardiac fibrosis that progressed to heart failure and middle-aged death. Failing hearts from cardiomyocyte-restricted knockout mice displayed a general decline in mitochondrial gene expression and oxidative phosphorylation (OXPHOS) activity. Pre-DCM, we observed no defects in mitochondrial morphology, content, gene expression, OXPHOS assembly nor phosphorylation dependent respiration. However, knockout cardiac mitochondria displayed reduced membrane potential and increased non-phosphorylation dependent respiration, which could be rescued by pharmacological inhibition of the adenine nucleotide translocase ANT. Primary cardiomyocytes from pre-symptomatic knockout mice exhibited normal excitation-contraction coupling but increased sensitivity to programmed cell death (PCD), which was accompanied by an opening of the mitochondrial permeability transition pore (mPTP). Intriguingly, mouse embryonic fibroblasts deleted for Mtfp1 recapitulated PCD sensitivity and mPTP opening, both of which could be rescued by pharmacological or genetic inhibition of the mPTP regulator Cyclophilin D. Collectively, our data demonstrate that contrary to previous in vitro studies, the loss of the MTFP1 promotes mitochondrial uncoupling and increases cell death sensitivity, causally mediating pathogenic cardiac remodeling
2022-10-06 | PXD028529 | Pride
Project description:Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in adult-onset dilated cardiomyopathy (DCM) characterized by sterile inflammation and cardiac fibrosis that progressed to heart failure and middle-aged death. Failing hearts from cardiomyocyte-restricted knockout mice displayed a general decline in mitochondrial gene expression and oxidative phosphorylation (OXPHOS) activity. Pre-DCM, we observed no defects in mitochondrial morphology, content, gene expression, OXPHOS assembly nor phosphorylation dependent respiration. However, knockout cardiac mitochondria displayed reduced membrane potential and increased non-phosphorylation dependent respiration, which could be rescued by pharmacological inhibition of the adenine nucleotide translocase ANT. Primary cardiomyocytes from pre-symptomatic knockout mice exhibited normal excitation-contraction coupling but increased sensitivity to programmed cell death (PCD), which was accompanied by an opening of the mitochondrial permeability transition pore (mPTP). Intriguingly, mouse embryonic fibroblasts deleted for Mtfp1 recapitulated PCD sensitivity and mPTP opening, both of which could be rescued by pharmacological or genetic inhibition of the mPTP regulator Cyclophilin D. Collectively, our data demonstrate that contrary to previous in vitro studies, the loss of the MTFP1 promotes mitochondrial uncoupling and increases cell death sensitivity, causally mediating pathogenic cardiac remodeling.
2022-10-05 | PXD034477 | Pride
Project description:Background: Cardiac Ryanodine receptors (RyR2) can regulate Ca2+ release in the excitation-contraction coupling, when activated, it releases a large amount of Ca2+ into the cytoplasm. Additionally, studies have shown that dantrolene (a RyR2 inhibitor) protects against heart failure and arrhythmias by inhibiting domain decompression, Ca2+ leakage and diastolic Ca2+ sparking. However, the role and mechanism of dantrolene in cardiac hypertrophy remain unclear. Objective: In this study, we aimed to evaluate the therapeutic effects of dantrolene on pressure overload-induced cardiac hypertrophy in mice models by transverse aortic contraction (TAC) surgery and to explore its potential mechanism. Methods: C57/B6 mice (age: 8 weeks) underwent TAC or sham surgical procedure and were administered oral dantrolene (30 mg/kg) or the solvent drug postoperatively. After 4 weeks of drug treatment, RNA sequencing of mice left ventricle was performed.qRT–PCR validation was performed using SYBR Green assays. Results: We found that dantrolene significantly alleviated TAC-induced cardiac hypertrophy. According to RNA sequencing, 184 down-regulated genes were found after dantrolene treatment compared with TAC group, 8 of these were validated with qRT–PCR. According to the KEGG analysis, Creb3l3, IL18R1 and Ccl5 were down-regulated after dantrolene treatment, which were related to TNF-α pathway. Conclusion: As a RyR2 inhibitor, dantrolene attenuates cardiac hypetrophy through downregulating the TNF-α/NF-κB/NLRP3 signaling pathway.
2023-07-01 | GSE184769 | GEO