800. Knock Down Phospholamban To Improve Heart Function by AAV- and Adenovirus-Mediated RNAi

Chronic chagasic cardiomyopathy (CCM) is presented with ventricular hypertrophy and contractile dysfunction that can lead to heart failure. I have found that a substantial decline in mitochondrial biogenesis and SIRT1/PGC-1α activity ensue in chronic chagasic mice. It was evidenced by the decline in mitochondrial DNA content as well as mRNA levels of mitochondrial encoded genes and mtDNA replication machinery. Further, the activity of SIRT1 (required for PGC-1α activation) was decreased and associated with decreased nuclear levels of PGC-1-regulated NRF1 transcription factor in chagasic hearts. The mitochondrial size and number were also reduced in chagasic heart, determined by electron microscopy. Therefore, we hypothesized that enhancing the SIRT1/PGC-1α activity by SIRT1 agonist would improve heart function through activating mitochondrial biogenesis in Chagasic disease. Mice were infected with T. cruzi, and beginning at day 90 post-infection (pi), treated with resveratrol (SIRT1 agonist) or metformin (AMPK agonist, can enhance SIRT1 activity) for 21 days; and then heart function was monitored at 150 days pi. We found that treatment with resveratrol partially attenuated the heart dysfunction (stroke volume, cardiac output, ejection fraction, heart rate) and cardiac hypertrophy in chagasic mice. These benefits were associated with improved expression of the mitochondrial DNA encoded genes and mtDNA content though the expression of genes involved in mtDNA replication was not improved. Treatment with metformin was not significantly beneficial in improving the CCM outcomes. The partial beneficial effects of resveratrol could be due to inefficient activation of SIRT1 or delayed start of the treatment. We plan to treat mice with SIRT1 agonist SIRT1720 (10 fold more active than resveratrol) during the indeterminate phase of T. cruzi infection in next set of experiments. This study will improve our understanding of the molecular and immune mechanisms of chagasic heart disease and will provide a novel treatment for chronically-infected chagasic patients.

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Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1701416114 ◽

2017 ◽

Vol 114 (30) ◽

pp. E6250-E6259 ◽

Cited By ~ 24

Author(s):

Ana Maria Manso ◽

Hideshi Okada ◽

Francesca M. Sakamoto ◽

Emily Moreno ◽

Susan J. Monkley ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Heart Function ◽

Membrane Integrity ◽

Heart Muscle Cell ◽

Functional Changes ◽

Adhesion Sites ◽

Improve Heart Function ◽

Simultaneous Loss ◽

Protein Reduction ◽

Sarcolemmal Integrity

Continuous contraction–relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the muscle-specific β1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. β1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper β1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.

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Erratum: Bone Marrow Mesenchymal Stem Cells (BM-MSCs) Improve Heart Function in Swine Myocardial Infarction Model through Paracrine Effects

Scientific Reports ◽

10.1038/srep31528 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 9

Author(s):

Min Cai ◽

Rui Shen ◽

Lei Song ◽

Minjie Lu ◽

Jianguang Wang ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Heart Function ◽

Paracrine Effects ◽

Marrow Mesenchymal Stem Cells ◽

Improve Heart Function

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Myocardial-restricted ablation of the GTPase RAD results in a pro-adaptive heart response in mice

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.008782 ◽

2019 ◽

Vol 294 (28) ◽

pp. 10913-10927 ◽

Cited By ~ 2

Author(s):

Brooke M. Ahern ◽

Bryana M. Levitan ◽

Sudhakar Veeranki ◽

Mihir Shah ◽

Nemat Ali ◽

...

Keyword(s):

Adrenergic Receptor ◽

Contractile Function ◽

Heart Function ◽

Unmet Need ◽

Calcium Transient ◽

Adverse Outcomes ◽

Endoplasmic Reticulum Calcium ◽

Functional Remodeling ◽

Improve Heart Function ◽

Sustained Increase

Existing therapies to improve heart function target β-adrenergic receptor (β-AR) signaling and Ca2+ handling and often lead to adverse outcomes. This underscores an unmet need for positive inotropes that improve heart function without any adverse effects. The GTPase Ras associated with diabetes (RAD) regulates L-type Ca2+ channel (LTCC) current (ICa,L). Global RAD-knockout mice (gRAD−/−) have elevated Ca2+ handling and increased cardiac hypertrophy, but RAD is expressed also in noncardiac tissues, suggesting the possibility that pathological remodeling is due also to noncardiac effects. Here, we engineered a myocardial-restricted inducible RAD-knockout mouse (RADΔ/Δ). Using an array of methods and techniques, including single-cell electrophysiological and calcium transient recordings, echocardiography, and radiotelemetry monitoring, we found that RAD deficiency results in a sustained increase of inotropy without structural or functional remodeling of the heart. ICa,L was significantly increased, with RAD loss conferring a β-AR–modulated phenotype on basal ICa,L. Cardiomyocytes from RADΔ/Δ hearts exhibited enhanced cytosolic Ca2+ handling, increased contractile function, elevated sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2a) expression, and faster lusitropy. These results argue that myocardial RAD ablation promotes a beneficial elevation in Ca2+ dynamics, which would obviate a need for increased β-AR signaling to improve cardiac function.

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PEMANFAATAN SEL PUNCA PADA INFARK MIOKARD

JURNAL BIOMEDIK (JBM) ◽

10.35790/jbm.3.1.2011.854 ◽

2013 ◽

Vol 3 (1) ◽

Author(s):

Loretta C. Wangko ◽

J. H. Awaloei ◽

Janry A. Pangemanan

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Stem Cell ◽

Growth Factors ◽

Tissue Repair ◽

Heart Function ◽

Improve Heart Function ◽

Β Blockers ◽

Causes Of Deaths ◽

Myocardial Thickness

Abstract: World-wide, myocardial infarction and heart failure are still the leading causes of deaths and use up a great deal of money. In myocardial infarction there frequently incur cardiomyocyte injuries. Naturally, resident cardiomyocytes will undergo proliferation and contribute to the increasing and repairing of myocardium post infarction. Unfortunately, this capacity of regeneration is very limited. Moreover, injured cardiomyocytes are replaced by scar tissues. Pharmacotherapy with ACE-Inhibitors and β blockers can give some clinical improvement, but can not inhibit the loss of cardiomyocytes. Nowadays, stem cell therapy has proclaimed some promising benefits. Among all the introduced stem cells, mesenchymal stem cells are the most popular since they have the capability to differentiate and then to develop into cardiomyocytes, maintain the myocardial thickness, reduce heart remodeling of the non infarct myocardium, improve heart function, and can be used from allogenic donors. Besides that, these cells are easier to obtain and isolate, are genetically stable, have the capacity for angiogenesis, homing to the injured areas or inflammation, and supplying growth factors and cytokines for tissue repair. Key words: stem cell, cardiomyocyte, transplantation, donor. Abstrak: Infark miokard dan gagal jantung masih merupakan penyebab kematian utama di dunia dan menyerap biaya pengobatan yang tinggi. Pada infark miokard sering terjadi cedera kardiomiosit. Secara alamiah kardiomiosit residen akan mengalami proliferasi dan mengambil bagian dalam meningkatkan dan memulihkan miokard pasca infark. Kapasitas regenerasi ini sangat terbatas. Selain itu kardiomiosit yang cedera akan digantikan oleh jaringan ikat. Farmakoterapi dengan penghambat ACE dan β bloker dapat memberikan perbaikan klinis, tetapi tidak dapat menghambat kehilangan kardiomiosit. Dewasa ini terapi sel punca telah mengumandangkan manfaat yang menjanjikan. Dari berbagai sel punca yang dikemukakan, sel punca mesensimal yang paling diminati oleh karena kemampuannya berdiferensiasi dan berkembang menjadi kardiomiosit, mempertahankan ketebalan miokard, menurunkan remodeling jantung pada bagian yang tidak infark, memperbaiki fungsi jantung. dan dapat diambil dari donor alogenik. Disamping itu, sel-sel ini lebih mudah diperoleh dan diisolasi, stabil secara genetik, berkapasitas angiogenesis, homing ke tempat cedera atau inflamasi, dan memasok growth factors dan sitokin untuk perbaikan jaringan. Kata kunci: sel punca, kardiomiosit, transplantasi, donor.

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