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Journal of molecular and cellular cardiology 9건

  1. [해외논문]   Title page (with Ed. Board)   SCI SCIE


    Journal of molecular and cellular cardiology v.120 ,pp. i - i , 2018 , 0022-2828 ,

    초록

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  2. [해외논문]   TRPV6 protects ER stress-induced apoptosis via ATF6α-TRPV6-JNK pathway in human embryonic stem cell-derived cardiomyocytes   SCI SCIE

    Li, Zhichao (School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China ) , Meng, Zhaoyue (School of Life Sciences and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China ) , Lu, Jun (School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China ) , Chen, Francis M. (School of Life Sciences and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China ) , Wong, Wing-Tak (School of Life Sciences and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China ) , Tse, Gary (Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China ) , Zheng, Changbo (School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China ) , Keung, Wendy (Dr. Li Dak-Sum Centre, The University of Hong Kong –) , Tse, Kennis (Karolinska Institutet Collaboration in Regenerative Medicine, Hong Kong, China ) , Li, Ronald A. (Dr. Li Dak-Sum Centre, The University of Hong Kong –) , Jiang, Liwen (Karolinska Institutet Collaboration in Regenerative Medicine) , Yao, Xiaoqiang
    Journal of molecular and cellular cardiology v.120 ,pp. 1 - 11 , 2018 , 0022-2828 ,

    초록

    Abstract Human pluripotent stem cell-derived cardiomyocytes have potential applications in disease modeling and drug screening. Therefore, it is important to understand the mechanisms and signaling pathways underlying the survival and death of these cells. Endoplasmic reticulum (ER) stress is triggered by various cellular stresses that disturb protein folding in the ER. Cells cope with ER stress by activating the unfolded protein response (UPR), a homeostatic signaling network that orchestrates the recovery of ER function. In the present study, we hypothesized that ER stress may upregulate the expression of transient receptor potential channel TRPV6, which in turn serves to protect human embryonic stem cell-derived cardiomyocytes (hESC-CMs) from ER stress-induced apoptotic cell death. Indeed, we found that ER stress induced by thapsigargin and tunicamycin led to increased expression of TRPV6 via ATF6α signaling branch. siRNA-mediated knockdown of TRPV6 aggravated ER stress-induced apoptotic cell death, whereas overexpression of TRPV6 attenuated ER stress-induced apoptosis in hESC-CMs. Furthermore, the signaling pathway downstream of TRPV6 was MAPK-JNK. Taken together, these results provide strong evidence that, under ER stress, TRPV6 is upregulated to protect hESC-CMs from apoptotic cell death via ATF6α-TRPV6-JNK pathway. Highlights ER stress increases the expression of TRPV6 in hESC-CMs. ER stress-induced upregulation of TRPV6 is via ATF6α signaling branch. TRPV6 protects hESC-CMs from ER stress-induced apoptotic cell death. The signaling pathway involves ATF6α-TRPV6-JNK.

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  3. [해외논문]   Myocardial infarction-induced hippocampal microtubule damage by cardiac originating microRNA-1 in mice   SCI SCIE

    Sun, Lin-Lin (Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China ) , Duan, Ming-Jing (Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China ) , Ma, Ji-Chao (Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China ) , Xu, Ling (Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China ) , Mao, Meng (Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province 150086, China ;) , Biddyut, Das , Wang, Qin , Yang, Chao , Zhang, Shuai , Xu, Yi , Yang, Lin , Tian, You , Liu, Ying , Xia, Sheng-Nan , Li, Ke-Xin , Jin, Zhuo , Xiong, Qiaojie , Ai, Jing
    Journal of molecular and cellular cardiology v.120 ,pp. 12 - 27 , 2018 , 0022-2828 ,

    초록

    Abstract Cardiovascular diseases are risk factors for dementia, but the mechanisms remain elusive. Here, we report that myocardial infarction (MI) generated by the ligation of the left coronary artery (LCA) could lead to increased miR-1 levels in the hippocampus and blood with neuronal microtubule damage and decreased TPPP/p25 protein expression in the hippocampus. These changes could be prevented by a knockdown of miR-1 using hippocampal stereotaxic injections of anti- miR-1 oligonucleotide fragments carried by a lentivirus vector (lenti-pre-AMO- miR-1 ). TPPP/p25 protein was downregulated by miR-1 overexpression, upregulated by miR-1 inhibition, and unchanged by binding-site mutations or miR-masks, indicating that the TPPP/p25 gene was a potential target for miR-1 . Additionally, the pharmacological inhibition of sphingomyelinase by GW4869 to inhibit exosome generation in the heart significantly attenuated the increased miR-1 levels in the hippocampi of transgenic (Tg) and MI mice. Collectively, the present study demonstrates that MI could directly lead to neuronal microtubule damage independent of MI-induced chronic brain hypoperfusion but involving the overexpression of miR-1 in the hippocampus that was transported by exosomes from infarcted hearts. This study reveals a novel insight into the molecular mechanisms of heart-to-brain communication at the miRNA level. Highlights Myocardial infarction leads to miR-1 overexpression in hippocampus. Exosome transports miR-1 from the heart to brain. Myocardial infarction induces neuronal microtubule damage in hippocampus. miR-1 results neuronal microtubule damage by downregulating TPPP/p25 protein. Graphical abstract [DISPLAY OMISSION]

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  4. [해외논문]   Adjusted analysis   SCI SCIE

    Lee, Paul H.
    Journal of molecular and cellular cardiology v.120 ,pp. 28 - 30 , 2018 , 0022-2828 ,

    초록

    Abstract Cardiovascular diseases are risk factors for dementia, but the mechanisms remain elusive. Here, we report that myocardial infarction (MI) generated by the ligation of the left coronary artery (LCA) could lead to increased miR-1 levels in the hippocampus and blood with neuronal microtubule damage and decreased TPPP/p25 protein expression in the hippocampus. These changes could be prevented by a knockdown of miR-1 using hippocampal stereotaxic injections of anti- miR-1 oligonucleotide fragments carried by a lentivirus vector (lenti-pre-AMO- miR-1 ). TPPP/p25 protein was downregulated by miR-1 overexpression, upregulated by miR-1 inhibition, and unchanged by binding-site mutations or miR-masks, indicating that the TPPP/p25 gene was a potential target for miR-1 . Additionally, the pharmacological inhibition of sphingomyelinase by GW4869 to inhibit exosome generation in the heart significantly attenuated the increased miR-1 levels in the hippocampi of transgenic (Tg) and MI mice. Collectively, the present study demonstrates that MI could directly lead to neuronal microtubule damage independent of MI-induced chronic brain hypoperfusion but involving the overexpression of miR-1 in the hippocampus that was transported by exosomes from infarcted hearts. This study reveals a novel insight into the molecular mechanisms of heart-to-brain communication at the miRNA level. Highlights Myocardial infarction leads to miR-1 overexpression in hippocampus. Exosome transports miR-1 from the heart to brain. Myocardial infarction induces neuronal microtubule damage in hippocampus. miR-1 results neuronal microtubule damage by downregulating TPPP/p25 protein. Graphical abstract [DISPLAY OMISSION]

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  5. [해외논문]   Improving electrical properties of iPSC-cardiomyocytes by enhancing Cx43 expression   SCI SCIE

    Sottas, Valentin (Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany ) , Wahl, Carl-Mattheis (Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany ) , Trache, Mihnea C. (Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany ) , Bartolf-Kopp, Michael (Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany ) , Cambridge, Sidney (Institute of Anatomy, Functional Neuroanatomy, Heidelberg University, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany ) , Hecker, Markus (Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany ) , Ullrich, Nina D. (Institute of Physiology and Pathophysiology, Division of Cardiovascular Physi)
    Journal of molecular and cellular cardiology v.120 ,pp. 31 - 41 , 2018 , 0022-2828 ,

    초록

    Abstract The therapeutic potential of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is limited by immature functional features including low impulse propagation and reduced cell excitability. Key players regulating electrical activity are voltage-gated Na + channels (Na v 1.5) and gap junctions built from connexin-43 (Cx43). Here we tested the hypothesis that enhanced Cx43 expression increases intercellular coupling and influences excitability by modulating Na v 1.5. Using transgenic approaches, Cx43 and Na v 1.5 localization and cell coupling were studied by confocal imaging. Na v 1.5 currents and action potentials (APs) were measured using the patch-clamp technique. Enhanced sarcolemmal Cx43 expression significantly improved intercellular coupling and accelerated dye transfer kinetics. Furthermore, Cx43 modulated Na v 1.5 function leading to significantly higher current and enhanced AP upstroke velocities, thereby improving electrical activity as measured by microelectrode arrays. These findings suggest a mechanistic link between cell coupling and excitability controlled by Cx43 expression in iPSC-CMs. Therefore, we propose Cx43 as novel molecular target for improving electrical properties of iPSC-CMs to match the functional properties of native myocytes. Highlights Enhanced Cx43 expression leads to increased gap junction formation in iPSC-CMs. Spatio-temporal characteristics of signal propagation are significantly improved. Cx43 expression co-regulates Na v 1.5 ion channel function and myocyte excitability.

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  6. [해외논문]   Mutation of the Na+/K+-ATPase Atp1a1a.1 causes QT interval prolongation and bradycardia in zebrafish   SCI SCIE

    Pott, Alexander (Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany ) , Bock, Sarah (Molecular Cardiology, Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany ) , Berger, Ina M. (Molecular Cardiology, Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany ) , Frese, Karen (Department of Internal Medicine III, Heidelberg University Medical Center, Heidelberg, Germany ) , Dahme, Tillman (Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany ) , Keßler, Mirjam (Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany ) , Rinné (Institute for Physiology and Pathophysiology, AG Vegetative Physiology, Philipps-University of Marburg, Marburg, Germany ) , , Susanne (Institute for Physiology and Pathophysiology, AG Vegetative Physiology, Philipps-University of Marburg, Marburg, Germany ) , Decher, Niels (Molecular Cardiology, Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany ) , Just, Steffen (Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany) , Rottbauer, Wolfgang
    Journal of molecular and cellular cardiology v.120 ,pp. 42 - 52 , 2018 , 0022-2828 ,

    초록

    Abstract The genetic underpinnings that orchestrate the vertebrate heart rate are not fully understood yet, but of high clinical importance, since diseases of cardiac impulse formation and propagation are common and severe human arrhythmias. To identify novel regulators of the vertebrate heart rate, we deciphered the pathogenesis of the bradycardia in the homozygous zebrafish mutant hiphop (hip) and identified a missense-mutation (N851K) in Na + /K + -ATPase α1-subunit (atp1a1a.1). N851K affects zebrafish Na + /K + -ATPase ion transport capacity, as revealed by in vitro pump current measurements. Inhibition of the Na + /K + -ATPase in vivo indicates that hip rather acts as a hypomorph than being a null allele. Consequently, reduced Na + /K + -ATPase function leads to prolonged QT interval and refractoriness in the hip mutant heart, as shown by electrocardiogram and in vivo electrical stimulation experiments. We here demonstrate for the first time that Na + /K + -ATPase plays an essential role in heart rate regulation by prolonging myocardial repolarization. Highlights Genetic and molecular underpinnings of heart rate regulation is not fully understood yet Zebrafish has emerged as a valuable model to systematically dissect pathomechanisms of human arrhythmias N851K mutation leads to loss of Na + /K + -ATPase function in the zebrafish mutant hiphop In vitro assays demonstrate reduced hiphop Na + /K + -ATPase transmembranous pump currents Reduced Na + /K + -ATPase activity causes prolonged QT interval and myocardial refractoriness in hiphop resulting in severe bradycardia and atrioventricular block

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  7. [해외논문]   Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats   SCI SCIE

    Stenzig, Justus (Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany ) , Schneeberger, Yvonne (Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany ) , Lö (Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany ) , ser, Alexandra (Department of Cardiovascular Medicine, Institute of Physiology, University of Greifswald, 17495 Karlsburg, Germany ) , Peters, Barbara S. (DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany ) , Schaefer, Andreas (Genome Institute of Singapore, 138672, Singapore ) , Zhao, Rong-Rong (Cardiovascular Research Institute, National University of Singapore, 117599, Singapore ) , Ng, Shi Ling (Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany ) , Hö (Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany ) , ppner, Grit (Depar) , Geertz, Birgit , Hirt, Marc N. , Tan, Wilson , Wong, Eleanor , Reichenspurner, Hermann , Foo, Roger S.-Y. , Eschenhagen, Thomas
    Journal of molecular and cellular cardiology v.120 ,pp. 53 - 63 , 2018 , 0022-2828 ,

    초록

    Abstract Background Heart failure is associated with altered gene expression and DNA methylation. De novo DNA methylation is associated with gene silencing, but its role in cardiac pathology remains incompletely understood. We hypothesized that inhibition of DNA methyltransferases (DNMT) might prevent the deregulation of gene expression and the deterioration of cardiac function under pressure overload (PO). To test this hypothesis, we evaluated a DNMT inhibitor in PO in rats and analysed DNA methylation in cardiomyocytes. Methods and results Young male Wistar rats were subjected to PO by transverse aortic constriction (TAC) or to sham surgery. Rats from both groups received solvent or 12.5 mg/kg body weight of the non-nucleosidic DNMT inhibitor RG108, initiated on the day of the intervention. After 4 weeks, we analysed cardiac function by MRI, fibrosis with Sirius Red staining, gene expression by RNA sequencing and qPCR, and DNA methylation by reduced representation bisulphite sequencing (RRBS). RG108 attenuated the ~70% increase in heart weight/body weight ratio of TAC over sham to 47% over sham, partially rescued reduced contractility, diminished the fibrotic response and the downregulation of a set of genes including Atp2a2 (SERCA2a) and Adrb1 (beta1-adrenoceptor). RG108 was associated with significantly lower global DNA methylation in cardiomyocytes by ~2%. The differentially methylated pathways were “cardiac hypertrophy”, “cell death” and “xenobiotic metabolism signalling”. Among these, “cardiac hypertrophy” was associated with significant methylation differences in the group comparison sham vs. TAC, but not significant between sham+RG108 and TAC+RG108 treatment, suggesting that RG108 partially prevented differential methylation. However, when comparing TAC and TAC+RG108, the pathway cardiac hypertrophy was not significantly differentially methylated. Conclusions DNMT inhibitor treatment is associated with attenuation of cardiac hypertrophy and moderate changes in cardiomyocyte DNA methylation. The potential mechanistic link between these two effects and the role of non-myocytes need further clarification. Highlights Cardiac hypertrophy in rats is associated with altered cardiomyocyte DNA methylation. DNA methylation changes in cardiomyocytes in hypertrophy map to relevant pathways. DNA methyltransferase inhibition in all cell types in hypertrophy partially rescues heart function.

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  8. [해외논문]   Regulation of cardiac fibroblast MMP2 gene expression by scleraxis   SCI SCIE

    Nagalingam, Raghu S. (Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada ) , Safi, Hamza A. (Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada ) , Al-Hattab, Danah S. (Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada ) , Bagchi, Rushita A. (Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada ) , Landry, Natalie M. (Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada ) , Dixon, Ian M.C. (Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada ) , Wigle, Jeffrey T. (Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada ) , Czubryt, Michael P. (Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, W)
    Journal of molecular and cellular cardiology v.120 ,pp. 64 - 73 , 2018 , 0022-2828 ,

    초록

    Abstract Remodeling of the cardiac extracellular matrix is responsible for a number of the detrimental effects on heart function that arise secondary to hypertension, diabetes and myocardial infarction. This remodeling consists both of an increase in new matrix protein synthesis, and an increase in the expression of matrix metalloproteinases (MMPs) that degrade existing matrix structures. Previous studies utilizing knockout mice have demonstrated clearly that MMP2 plays a pathogenic role during matrix remodeling, thus it is important to understand the mechanisms that regulate MMP2 gene expression. We have shown that the transcription factor scleraxis is an important inducer of extracellular matrix gene expression in the heart that may also control MMP2 expression. In the present study, we demonstrate that scleraxis directly transactivates the proximal MMP2 gene promoter, resulting in increased histone acetylation, and identify a specific E-box sequence in the promoter to which scleraxis binds. Cardiac myo-fibroblasts isolated from scleraxis knockout mice exhibited dramatically decreased MMP2 expression; however, scleraxis over-expression in knockout cells could rescue this loss. We further show that regulation of MMP2 gene expression by the pro-fibrotic cytokine TGFβ occurs via a scleraxis-dependent mechanism: TGFβ induces recruitment of scleraxis to the MMP2 promoter, and TGFβ was unable to up-regulate MMP2 expression in cells lacking scleraxis due to either gene knockdown or knockout. These results reveal that scleraxis can exert control over both extracellular matrix synthesis and breakdown, and thus may contribute to matrix remodeling in wound healing and disease. Highlights Scleraxis regulates MMP2 expression in cardiac myo-fibroblasts. Scleraxis binds E-box 6 in the proximal human MMP2 promoter to control transcription. Over-expression of scleraxis increases MMP2 promoter histone acetylation at H3K9. Loss of scleraxis expression results in loss of MMP2 expression. TGFβ-mediated MMP2 expression requires the presence of scleraxis.

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  9. [해외논문]   Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension   SCI SCIE

    Fowler, Ewan D. (Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK ) , Drinkhill, Mark J. (Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK ) , Norman, Ruth (Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK ) , Pervolaraki, Eleftheria (Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK ) , Stones, Rachel (Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK ) , Steer, Emma (Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK ) , Benoist, David (Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK ) , Steele, Derek S. (Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK ) , Calaghan, Sarah C. (Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK ) , White, Ed (Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK)
    Journal of molecular and cellular cardiology v.120 ,pp. 74 - 83 , 2018 , 0022-2828 ,

    초록

    Abstract Right heart failure is the major cause of death in Pulmonary Artery Hypertension (PAH) patients but is not a current, specific therapeutic target. Pre-clinical studies have shown that adrenoceptor blockade can improve cardiac function but the mechanisms of action within right ventricular (RV) myocytes are unknown. We tested whether the β 1 –adrenoceptor blocker metoprolol could improve RV myocyte function in an animal model of PAH, by attenuating adverse excitation-contraction coupling remodeling. PAH with RV failure was induced in rats by monocrotaline injection. When PAH was established, animals were given 10 mg/kg/day metoprolol (MCT + BB) or vehicle (MCT). The median time to the onset of heart failure signs was delayed from 23 days (MCT), to 31 days (MCT + BB). At 23 ± 1 days post-injection, MCT + BB showed improved in vivo cardiac function, measured by echocardiography. RV hypertrophy was reduced despite persistent elevated afterload. RV myocyte contractility during field stimulation was improved at higher pacing frequencies in MCT + BB. Preserved t-tubule structure, more uniform evoked Ca 2+ release, increased SERCA2a expression and faster ventricular repolarization (measured in vivo by telemetry) may account for the improved contractile function. Sarcoplasmic reticulum Ca 2+ overload was prevented in MCT + BB myocytes resulting in fewer spontaneous Ca 2+ waves, with a lower pro-arrhythmic potential. Our novel finding of attenuation of defects in excitation contraction coupling by β 1 –adrenoceptor blockade with delays in the onset of HF, identifies the RV as a promising therapeutic target in PAH. Moreover, our data suggest existing therapies for left ventricular failure may also be beneficial in PAH induced RV failure. Highlights β 1 –adrenoceptor blocker metoprolol delayed the onset of right heart failure in PAH rats. Metoprolol attenuated repolarisation remodelling, measured in vivo by telemetry. Metoprolol attenuated t-tubule remodeling in single right ventricular myocytes. Metoprolol attenuating adverse Ca 2+ handling remodeling in right ventricular myocytes. β–adrenoceptor blockade may be a useful additional treatment for PAH.

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