Displaying publications 1 - 20 of 51 in total

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  1. Dental stem cells as an alternative source for cardiac regeneration
    Xin LZ, Govindasamy V, Musa S, Abu Kasim NH
    Med Hypotheses, 2013 Oct;81(4):704-6.
    PMID: 23932760 DOI: 10.1016/j.mehy.2013.07.032
    Dental tissues contains stem cells or progenitors that have high proliferative capacity, are clonogenic in vitro and demonstrate the ability to differentiate to multiple type cells involving neurons, bone, cartilage, fat and smooth muscle. Numerous experiments have demonstrated that the multipotent stem cells are not rejected by immune system and therefore it may be possible to use these cells in allogeneic settings. In addition, these remarkable cells are easily abundantly available couple with less invasive procedure in isolating comparing to bone marrow aspiration. Here we proposed dental stem cells as candidate for cardiac regeneration based on its immature characteristic and propensity towards cardiac lineage via PI3-Kinase/Aktsignalling pathway.
    Matched MeSH terms: Myocytes, Cardiac/physiology
  2. Fulltext 5-Azacytidine is insufficient for cardiogenesis in human adipose-derived stem cells
    Wan Safwani WK, Makpol S, Sathapan S, Chua KH
    J Negat Results Biomed, 2012;11:3.
    PMID: 22221649 DOI: 10.1186/1477-5751-11-3
    Adipose tissue is a source of multipotent adult stem cells and it has the ability to differentiate into several types of cell lineages such as neuron cells, osteogenic cells and adipogenic cells. Several reports have shown adipose-derived stem cells (ASCs) have the ability to undergo cardiomyogenesis. Studies have shown 5-azacytidine can successfully drive stem cells such as bone marrow derived stem cells to differentiate into cardiomyogenic cells. Therefore, in this study, we investigated the effect 5-azacytidine on the cardiogenic ability of ASCs.
    Matched MeSH terms: Myocytes, Cardiac/cytology*; Myocytes, Cardiac/drug effects; Myocytes, Cardiac/metabolism
  3. Fulltext Heart and bile acids - Clinical consequences of altered bile acid metabolism
    Vasavan T, Ferraro E, Ibrahim E, Dixon P, Gorelik J, Williamson C
    Biochim Biophys Acta Mol Basis Dis, 2018 04;1864(4 Pt B):1345-1355.
    PMID: 29317337 DOI: 10.1016/j.bbadis.2017.12.039
    Cardiac dysfunction has an increased prevalence in diseases complicated by liver cirrhosis such as primary biliary cholangitis and primary sclerosing cholangitis. This observation has led to research into the association between abnormalities in bile acid metabolism and cardiac pathology. Approximately 50% of liver cirrhosis cases develop cirrhotic cardiomyopathy. Bile acids are directly implicated in this, causing QT interval prolongation, cardiac hypertrophy, cardiomyocyte apoptosis and abnormal haemodynamics of the heart. Elevated maternal serum bile acids in intrahepatic cholestasis of pregnancy, a disorder which causes an impaired feto-maternal bile acid gradient, have been associated with fatal fetal arrhythmias. The hydrophobicity of individual bile acids in the serum bile acid pool is of relevance, with relatively lipophilic bile acids having a more harmful effect on the heart. Ursodeoxycholic acid can reverse or protect against these detrimental cardiac effects of elevated bile acids.
    Matched MeSH terms: Myocytes, Cardiac/pathology
  4. Fulltext Epac-induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes
    Valli H, Ahmad S, Sriharan S, Dean LD, Grace AA, Jeevaratnam K, et al.
    Clin Exp Pharmacol Physiol, 2018 03;45(3):278-292.
    PMID: 29027245 DOI: 10.1111/1440-1681.12870
    Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca2+ homeostasis, slows myocardial action potential conduction, and exerts pro-arrhythmic effects. Loose patch-clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na+ current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage-dependent Na+ currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of -20.23 ± 1.48 (17) and -29.8 ± 2.4 (10) pA/μm2 (mean ± SEM [n]). Challenge by 8-CPT (1 μmol/L) reduced these currents to -11.21 ± 0.91 (12) (P  .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half-maximal inactivation voltages and steepness factors, and time constants for Na+ current recovery from inactivation in double-pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff-perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (dV/dt)max . We thus demonstrate an acute, reversible, Na+ channel inhibition offering a possible mechanism for previously reported pro-arrhythmic slowing of AP propagation following modifications of Ca2+ homeostasis, complementing earlier findings from chronic alterations in Ca2+ homeostasis in genetically-modified RyR2-P2328S hearts.
    Matched MeSH terms: Myocytes, Cardiac/drug effects*; Myocytes, Cardiac/metabolism
  5. Fulltext Cardiomyocyte ionic currents in intact young and aged murine Pgc-1β-/- atrial preparations
    Valli H, Ahmad S, Jiang AY, Smyth R, Jeevaratnam K, Matthews HR, et al.
    Mech Ageing Dev, 2018 01;169:1-9.
    PMID: 29197478 DOI: 10.1016/j.mad.2017.11.016
    INTRODUCTION: Recent studies reported that energetically deficient murine Pgc-1β-/- hearts replicate age-dependent atrial arrhythmic phenotypes associated with their corresponding clinical conditions, implicating action potential (AP) conduction slowing consequent upon reduced AP upstroke rates.

    MATERIALS AND METHODS: We tested a hypothesis implicating Na+ current alterations as a mechanism underlying these electrophysiological phenotypes. We applied loose patch-clamp techniques to intact young and aged, WT and Pgc-1β-/-, atrial cardiomyocyte preparations preserving their in vivo extracellular and intracellular conditions.

    RESULTS AND DISCUSSION: Depolarising steps activated typical voltage-dependent activating and inactivating inward (Na+) currents whose amplitude increased or decreased with the amplitudes of the activating, or preceding inactivating, steps. Maximum values of peak Na+ current were independently influenced by genotype but not age or interacting effects of genotype and age on two-way ANOVA. Neither genotype, nor age, whether independently or interactively, influenced voltages at half-maximal current, or steepness factors, for current activation and inactivation, or time constants for recovery from inactivation following repolarisation. In contrast, delayed outward (K+) currents showed similar activation and rectification properties through all experimental groups. These findings directly demonstrate and implicate reduced Na+ in contrast to unchanged K+ current, as a mechanism for slowed conduction causing atrial arrhythmogenicity in Pgc-1β-/- hearts.

    Matched MeSH terms: Myocytes, Cardiac/metabolism*; Myocytes, Cardiac/pathology
  6. Fulltext Cytoprotective and Cytotoxic Effects of Rice Bran Extracts in Rat H9c2(2-1) Cardiomyocytes
    Tan XW, Bhave M, Fong AY, Matsuura E, Kobayashi K, Shen LH, et al.
    Oxid Med Cell Longev, 2016;2016:6943053.
    PMID: 27239253 DOI: 10.1155/2016/6943053
    This study was aimed at preliminarily assessing the cytoprotective and antioxidative effects of rice bran extracts (RBEs) from a Sarawak local rice variety (local name: "BJLN") and a commercial rice variety, "MR219," on oxidative stress in rat H9c2(2-1) cardiomyocytes. The cardiomyocytes were incubated with different concentrations of RBE and hydrogen peroxide (H2O2), respectively, to identify their respective IC50 values and safe dose ranges. Two nonlethal and close-to-IC50 doses of RBE were selected to evaluate their respective effects on H2O2 induced oxidative stress in cardiomyocytes. Both RBEs showed dose-dependent cytotoxicity effects on cardiomyocytes. H2O2 induction of cardiomyocytes pretreated with RBE further revealed the dose-dependent cytoprotective and antioxidative effects of RBE via an increase in IC50 values of H2O2. Preliminary analyses of induction effects of RBE and H2O2 on cellular antioxidant enzyme, catalase (CAT), also revealed their potential in regulating these activities and expression profile of related gene on oxidative stress in cardiomyocytes. Pretreated cardiomyocytes significantly upregulated the enzymatic activity and expression level of CAT under the exposure of H2O2 induced oxidative stress. This preliminary study has demonstrated the potential antioxidant effects of RBE in alleviating H2O2-mediated oxidative injuries via upregulation in enzymatic activities and expression levels of CAT.
    Matched MeSH terms: Myocytes, Cardiac/cytology*; Myocytes, Cardiac/drug effects
  7. Fulltext Human iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro
    Tan JJ, Guyette JP, Miki K, Xiao L, Kaur G, Wu T, et al.
    Nat Commun, 2021 08 17;12(1):4997.
    PMID: 34404774 DOI: 10.1038/s41467-021-24921-z
    Epicardial formation is necessary for normal myocardial morphogenesis. Here, we show that differentiating hiPSC-derived lateral plate mesoderm with BMP4, RA and VEGF (BVR) can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) expressing WT1, TBX18, SEMA3D, and SCX within 7 days. BVR stimulation after Wnt inhibition of LPM demonstrates co-differentiation and spatial organization of PECs and cardiomyocytes (CMs) in a single 2D culture. Co-culture consolidates CMs into dense aggregates, which then form a connected beating syncytium with enhanced contractility and calcium handling; while PECs become more mature with significant upregulation of UPK1B, ITGA4, and ALDH1A2 expressions. Our study also demonstrates that PECs secrete IGF2 and stimulate CM proliferation in co-culture. Three-dimensional PEC-CM spheroid co-cultures form outer smooth muscle cell layers on cardiac micro-tissues with organized internal luminal structures. These characteristics suggest PECs could play a key role in enhancing tissue organization within engineered cardiac constructs in vitro.
    Matched MeSH terms: Myocytes, Cardiac/physiology*
  8. The design of a thermoresponsive surface for the continuous culture of human pluripotent stem cells
    Sung TC, Yang JS, Yeh CC, Liu YC, Jiang YP, Lu MW, et al.
    Biomaterials, 2019 Nov;221:119411.
    PMID: 31419657 DOI: 10.1016/j.biomaterials.2019.119411
    Commonly, stem cell culture is based on batch-type culture, which is laborious and expensive. We continuously cultured human pluripotent stem cells (hPSCs) on thermoresponsive dish surfaces, where hPSCs were partially detached on the same thermoresponsive dish by decreasing the temperature of the thermoresponsive dish to be below the lower critical solution temperature for only 30 min. Then, the remaining cells were continuously cultured in fresh culture medium, and the detached stem cells were harvested in the exchanged culture medium. hPSCs were continuously cultured for ten cycles on the thermoresponsive dish surface, which was prepared by coating the surface with poly(N-isopropylacrylamide-co-styrene) and oligovitronectin-grafted poly(acrylic acid-co-styrene) or recombinant vitronectin for hPSC binding sites to maintain hPSC pluripotency. After ten cycles of continuous culture on the thermoresponsive dish surface, the detached cells expressed pluripotency proteins and had the ability to differentiate into cells derived from the three germ layers in vitro and in vivo. Furthermore, the detached cells differentiated into specific cell lineages, such as cardiomyocytes, with high efficiency.
    Matched MeSH terms: Myocytes, Cardiac
  9. Efficient differentiation of human pluripotent stem cells into cardiomyocytes on cell sorting thermoresponsive surface
    Sung TC, Su HC, Ling QD, Kumar SS, Chang Y, Hsu ST, et al.
    Biomaterials, 2020 09;253:120060.
    PMID: 32450407 DOI: 10.1016/j.biomaterials.2020.120060
    The current differentiation process of human pluripotent stem cells (hPSCs) into cardiomyocytes to enhance the purity of hPSC-derived cardiomyocytes requires some purification processes, which are laborious processes. We developed cell sorting plates, which are prepared from coating thermoresponsive poly(N-isopropylacrylamide) and extracellular matrix proteins. After hPSCs were induced into cardiomyocytes on the thermoresponsive surface coated with laminin-521 for 15 days, the temperature of the cell culture plates was decreased to 8-9 °C to detach the cells partially from the thermoresponsive surface. The detached cells exhibited a higher cardiomyocyte marker of cTnT than the remaining cells on the thermoresponsive surface as well as the cardiomyocytes after purification using conventional cell selection. The detached cells expressed several cardiomyocyte markers, such as α-actinin, MLC2a and NKX2.5. This study suggested that the purification of hPSC-derived cardiomyocytes using cell sorting plates with the thermoresponsive surface is a promising method for the purification of hPSC-derived cardiomyocytes without conventional laborious processes.
    Matched MeSH terms: Myocytes, Cardiac
  10. Efficient differentiation of human ES and iPS cells into cardiomyocytes on biomaterials under xeno-free conditions
    Sung TC, Liu CH, Huang WL, Lee YC, Kumar SS, Chang Y, et al.
    Biomater Sci, 2019 Oct 28.
    PMID: 31656967 DOI: 10.1039/c9bm00817a
    Current xeno-free and chemically defined methods for the differentiation of hPSCs (human pluripotent stem cells) into cardiomyocytes are not efficient and are sometimes not reproducible. Therefore, it is necessary to develop reliable and efficient methods for the differentiation of hPSCs into cardiomyocytes for future use in cardiovascular research related to drug discovery, cardiotoxicity screening, and disease modeling. We evaluated two representative differentiation methods that were reported previously, and we further developed original, more efficient methods for the differentiation of hPSCs into cardiomyocytes under xeno-free, chemically defined conditions. The developed protocol successively differentiated hPSCs into cardiomyocytes, approximately 90-97% of which expressed the cardiac marker cTnT, with beating speeds and sarcomere lengths that were similar to those of a healthy adult human heart. The optimal cell culture biomaterials for the cardiac differentiation of hPSCs were also evaluated using extracellular matrix-mimetic material-coated dishes. Synthemax II-coated and Laminin-521-coated dishes were found to be the most effective and efficient biomaterials for the cardiac differentiation of hPSCs according to the observation of hPSC-derived cardiomyocytes with high survival ratios, high beating colony numbers, a similar beating frequency to that of a healthy adult human heart, high purity levels (high cTnT expression) and longer sarcomere lengths similar to those of a healthy adult human heart.
    Matched MeSH terms: Myocytes, Cardiac
  11. Fulltext TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy
    Sudi SB, Tanaka T, Oda S, Nishiyama K, Nishimura A, Sunggip C, et al.
    Sci Rep, 2019 07 05;9(1):9785.
    PMID: 31278358 DOI: 10.1038/s41598-019-46252-2
    Myocardial atrophy, characterized by the decreases in size and contractility of cardiomyocytes, is caused by severe malnutrition and/or mechanical unloading. Extracellular adenosine 5'-triphosphate (ATP), known as a danger signal, is recognized to negatively regulate cell volume. However, it is obscure whether extracellular ATP contributes to cardiomyocyte atrophy. Here, we report that ATP induces atrophy of neonatal rat cardiomyocytes (NRCMs) without cell death through P2Y2 receptors. ATP led to overproduction of reactive oxygen species (ROS) through increased amount of NADPH oxidase (Nox) 2 proteins, due to increased physical interaction between Nox2 and canonical transient receptor potential 3 (TRPC3). This ATP-mediated formation of TRPC3-Nox2 complex was also pathophysiologically involved in nutritional deficiency-induced NRCM atrophy. Strikingly, knockdown of either TRPC3 or Nox2 suppressed nutritional deficiency-induced ATP release, as well as ROS production and NRCM atrophy. Taken together, we propose that TRPC3-Nox2 axis, activated by extracellular ATP, is the key component that mediates nutritional deficiency-induced cardiomyocyte atrophy.
    Matched MeSH terms: Myocytes, Cardiac/metabolism*; Myocytes, Cardiac/pathology
  12. Fulltext Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice
    Shimoda K, Nishimura A, Sunggip C, Ito T, Nishiyama K, Kato Y, et al.
    Sci Rep, 2020 08 18;10(1):13926.
    PMID: 32811872 DOI: 10.1038/s41598-020-70956-5
    Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.
    Matched MeSH terms: Myocytes, Cardiac/metabolism
  13. Fulltext Graphene Oxide-Gold Nanosheets Containing Chitosan Scaffold Improves Ventricular Contractility and Function After Implantation into Infarcted Heart
    Saravanan S, Sareen N, Abu-El-Rub E, Ashour H, Sequiera GL, Ammar HI, et al.
    Sci Rep, 2018 10 10;8(1):15069.
    PMID: 30305684 DOI: 10.1038/s41598-018-33144-0
    Abnormal conduction and improper electrical impulse propagation are common in heart after myocardial infarction (MI). The scar tissue is non-conductive therefore the electrical communication between adjacent cardiomyocytes is disrupted. In the current study, we synthesized and characterized a conductive biodegradable scaffold by incorporating graphene oxide gold nanosheets (GO-Au) into a clinically approved natural polymer chitosan (CS). Inclusion of GO-Au nanosheets in CS scaffold displayed two fold increase in electrical conductivity. The scaffold exhibited excellent porous architecture with desired swelling and controlled degradation properties. It also supported cell attachment and growth with no signs of discrete cytotoxicity. In a rat model of MI, in vivo as well as in isolated heart, the scaffold after 5 weeks of implantation showed a significant improvement in QRS interval which was associated with enhanced conduction velocity and contractility in the infarct zone by increasing connexin 43 levels. These results corroborate that implantation of novel conductive polymeric scaffold in the infarcted heart improved the cardiac contractility and restored ventricular function. Therefore, our approach may be useful in planning future strategies to construct clinically relevant conductive polymer patches for cardiac patients with conduction defects.
    Matched MeSH terms: Myocytes, Cardiac
  14. MiD49 and MiD51: New mediators of mitochondrial fission and novel targets for cardioprotection
    Samangouei P, Crespo-Avilan GE, Cabrera-Fuentes H, Hernández-Reséndiz S, Ismail NI, Katwadi KB, et al.
    Cond Med, 2018 Aug;1(5):239-246.
    PMID: 30338314
    Acute myocardial infarction (AMI) and the heart failure (HF) that often follows are among the leading causes of death and disability worldwide. As such novel therapies are needed to reduce myocardial infarct (MI) size, and preserve left ventricular (LV) systolic function in order to reduce the propensity for HF following AMI. Mitochondria are dynamic organelles that can undergo morphological changes by two opposing processes, mitochondrial fusion and fission. Changes in mitochondrial morphology and turnover are a vital part of maintaining mitochondrial health, DNA stability, energy production, calcium homeostasis, cellular division, and differentiation, and disturbances in the balance of fusion and fission can predispose to mitochondrial dysfunction and cell death. Changes in mitochondrial morphology are governed by mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1) and mitochondrial fission proteins (Drp1, hFis1, and Mff). Recent experimental data suggest that mitochondria undergo fission during acute ischemia/reperfusion injury (IRI), generating fragmented dysfunctional mitochondrial and predisposing to cell death. We and others have shown that genetic and pharmacological inhibition of the mitochondrial fission protein Drp1 can protect cardiomyocytes from acute IRI and reduce MI size. Novel components of the mitochondrial fission machinery, mitochondrial dynamics proteins of 49 kDa (MiD49) and mitochondrial dynamics proteins of 51 kDa (MiD51), have been recently described, which have been shown to mediating mitochondrial fission by targeting Drp1 to the mitochondrial surface. In this review article, we provide an overview of MiD49 and MiD51, and highlight their potential as novel therapeutic targets for treating cardiovascular diseases such as AMI, anthracycline cardiomyopathy, and pulmonary arterial hypertension.
    Matched MeSH terms: Myocytes, Cardiac
  15. Fulltext Highlighting the effects of high-intensity interval training on the changes associated with hypertrophy, apoptosis, and histological proteins of the heart of old rats with type 2 diabetes
    Rami M, Ahmadi Hekmatikar A, Rahdar S, Marashi SS, Daud DMA
    Sci Rep, 2024 Mar 26;14(1):7133.
    PMID: 38531890 DOI: 10.1038/s41598-024-57119-6
    T2DM is known to cause disturbances in glucose homeostasis and negative changes in the heart muscle, while aging and diabetes are recognized risk factors for CVD. Given this, our study aims to investigate a method for controlling and managing CVDs induced by T2DM in elderly populations. To achieve this, we categorized 40 rats into 5 groups, including HAD (n = 8), HA (n = 8), AD (n = 8), AHT (n = 8), and ADT (n = 8). The exercise protocol consisted of eight weeks of HIIT (three sessions per week) performed at 90-95% of maximal speed. Following cardiac tissue extraction, we assessed the levels of IGF-1, PI3K, and AKT proteins using Western blot technique, and analyzed the histopathological variations of the heart tissue using H&E, Sudan Black, and Masson's trichrome tissue staining. The histological findings from our study demonstrated that T2DM had a significant impact on the development of pathological hypertrophy and fibrosis in the heart tissue of elderly individuals. However, HIIT not only effectively controlled pathological hypertrophy and fibrosis, but also induced physiological hypertrophy in the AHT and ADT groups compared to the HA and AD groups. Results from Sudan Black staining indicated that there was an increase in lipid droplet accumulation in the cytoplasm of cardiomyocytes and their nuclei in the HA and AD groups, while the accumulation of lipid droplets decreased significantly in the AHT and ADT groups. In both the AHT group and the ADT group, a single HIIT session led to a reduction in collagen fiber accumulation and fibrotic frameworks. Our research also revealed that diabetes caused a significant elevation in the levels of IGF-1, PI3K, and AKT proteins, but after eight weeks of HIIT, the levels of these proteins decreased significantly in the training groups. Overall, our findings suggest that HIIT may be a suitable non-pharmacological approach for improving histological and physiological changes in elderly individuals with T2DM. However, we recommend further research to examine the impact of HIIT training on both healthy and diseased elderly populations.
    Matched MeSH terms: Myocytes, Cardiac
  16. Fulltext Angiotensin II Type I Receptor Antagonism Attenuates Nicotine-Induced Cardiac Remodeling, Dysfunction, and Aggravation of Myocardial Ischemia-Reperfusion Injury in Rats
    Ramalingam A, Budin SB, Mohd Fauzi N, Ritchie RH, Zainalabidin S
    Front Pharmacol, 2019;10:1493.
    PMID: 31920673 DOI: 10.3389/fphar.2019.01493
    Increased exposure to nicotine contributes to the development of cardiac dysfunction by promoting oxidative stress, fibrosis, and inflammation. These deleterious events altogether render cardiac myocytes more susceptible to acute cardiac insults such as ischemia-reperfusion (I/R) injury. This study sought to elucidate the role of angiotensin II type I (AT1) receptors in cardiac injury resulting from prolonged nicotine administration in a rat model. Male Sprague-Dawley rats were given nicotine (0.6 mg/kg ip) for 28 days to induce cardiac dysfunction, alone or in combination with the AT1 receptor antagonist, irbesartan (10 mg/kg, po). Vehicle-treated rats were used as controls. Rat hearts isolated from each experimental group at study endpoint were examined for changes in function, histology, gene expression, and susceptibility against acute I/R injury determined ex vivo. Rats administered nicotine alone exhibited significantly increased cardiac expression of angiotensin II and angiotensin-converting enzyme (ACE) in addition to elevated systolic blood pressure (SBP) and heart rate. Furthermore, nicotine administration markedly reduced left ventricular (LV) performance with concomitant increases in myocardial oxidative stress, fibrosis, and inflammation. Concomitant treatment with irbesartan attenuated these effects, lowering blood pressure, heart rate, oxidative stress, and expression of fibrotic and inflammatory genes. Importantly, the irbesartan-treated group also manifested reduced susceptibility to I/R injury ex vivo. These findings suggest that AT1 receptors play an important role in nicotine-induced cardiac dysfunction, and pharmacological approaches targeting cardiac AT1 receptors may thus benefit patients with sustained exposure to nicotine.
    Matched MeSH terms: Myocytes, Cardiac
  17. Fulltext Targeting mitochondrial reactive oxygen species-mediated oxidative stress attenuates nicotine-induced cardiac remodeling and dysfunction
    Ramalingam A, Budin SB, Mohd Fauzi N, Ritchie RH, Zainalabidin S
    Sci Rep, 2021 07 05;11(1):13845.
    PMID: 34226619 DOI: 10.1038/s41598-021-93234-4
    Long-term nicotine intake is associated with an increased risk of myocardial damage and dysfunction. However, it remains unclear whether targeting mitochondrial reactive oxygen species (ROS) prevents nicotine-induced cardiac remodeling and dysfunction. This study investigated the effects of mitoTEMPO (a mitochondria-targeted antioxidant), and resveratrol (a sirtuin activator) , on nicotine-induced cardiac remodeling and dysfunction. Sprague-Dawley rats were administered 0.6 mg/kg nicotine daily with 0.7 mg/kg mitoTEMPO, 8 mg/kg resveratrol, or vehicle alone for 28 days. At the end of the study, rat hearts were collected to analyze the cardiac structure, mitochondrial ROS level, oxidative stress, and inflammation markers. A subset of rat hearts was perfused ex vivo to determine the cardiac function and myocardial susceptibility to ischemia-reperfusion injury. Nicotine administration significantly augmented mitochondrial ROS level, cardiomyocyte hypertrophy, fibrosis, and inflammation in rat hearts. Nicotine administration also induced left ventricular dysfunction, which was worsened by ischemia-reperfusion in isolated rat hearts. MitoTEMPO and resveratrol both significantly attenuated the adverse cardiac remodeling induced by nicotine, as well as the aggravation of postischemic ventricular dysfunction. Findings from this study show that targeting mitochondrial ROS with mitoTEMPO or resveratrol partially attenuates nicotine-induced cardiac remodeling and dysfunction.
    Matched MeSH terms: Myocytes, Cardiac/drug effects; Myocytes, Cardiac/metabolism
  18. Fulltext Impact of prolonged nicotine administration on myocardial function and susceptibility to ischaemia-reperfusion injury in rats
    Ramalingam A, Mohd Fauzi N, Budin SB, Zainalabidin S
    Basic Clin Pharmacol Toxicol, 2021 Feb;128(2):322-333.
    PMID: 32991780 DOI: 10.1111/bcpt.13500
    This study investigated the impact of prolonged nicotine administration on myocardial susceptibility to ischaemia-reperfusion (I/R) injury in a rat model and determined whether nicotine affects mitochondrial reactive oxygen species (ROS) production and permeability transition in rat hearts. Sprague-Dawley rats were administered 0.6 or 1.2 mg/kg nicotine for 28 days, and their hearts were isolated at end-point for assessment of myocardial susceptibility to I/R injury ex vivo. Rat heart mitochondria were also isolated from a subset of rats for analysis of mitochondrial ROS production and permeability transition. Compared to the vehicle controls, rat hearts isolated from nicotine-administered rats exhibited poorer left ventricular function that worsened over the course of I/R. Coronary flow rate was also severely impaired in the nicotine groups at baseline and this worsened after I/R. Nicotine administration significantly increased mitochondrial ROS production and permeability transition relative to the vehicle controls. Interestingly, pre-incubation of isolated mitochondria with ROS scavengers (superoxide dismutase and mitoTEMPO) significantly abolished nicotine-induced increase in mitochondria permeability transition in isolated rat heart mitochondria. Overall, our data showed that prolonged nicotine administration enhances myocardial susceptibility to I/R injury in rats and this is associated with mitochondrial ROS-driven increase in mitochondrial permeability transition.
    Matched MeSH terms: Myocytes, Cardiac/drug effects*; Myocytes, Cardiac/metabolism; Myocytes, Cardiac/pathology
  19. Non-coding RNAs as therapeutic targets for preventing myocardial ischemia-reperfusion injury
    Ong SB, Katwadi K, Kwek XY, Ismail NI, Chinda K, Ong SG, et al.
    Expert Opin Ther Targets, 2018 03;22(3):247-261.
    PMID: 29417868 DOI: 10.1080/14728222.2018.1439015
    INTRODUCTION: New treatments are required to improve clinical outcomes in patients with acute myocardial infarction (AMI), for reduction of myocardial infarct (MI) size and preventing heart failure. Following AMI, acute ischemia/reperfusion injury (IRI) ensues, resulting in cardiomyocyte death and impaired cardiac function. Emerging studies have implicated a fundamental role for non-coding RNAs (microRNAs [miRNA], and more recently long non-coding RNAs [lncRNA]) in the setting of acute myocardial IRI. Areas covered: In this article, we discuss the roles of miRNAs and lncRNAs as potential biomarkers and therapeutic targets for the detection and treatment of AMI, review their roles as mediators and effectors of cardioprotection, particularly in the settings of interventions such as ischemic pre- and post-conditioning (IPC & IPost) as well as remote ischemic conditioning (RIC), and highlight future strategies for targeting ncRNAs to reduce MI size and prevent heart failure following AMI. Expert opinion: Investigating the roles of miRNAs and lncRNAs in the setting of AMI has provided new insights into the pathophysiology underlying acute myocardial IRI, and has identified novel biomarkers and therapeutic targets for detecting and treating AMI. Pharmacological and genetic manipulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients.
    Matched MeSH terms: Myocytes, Cardiac/pathology
  20. Guided evaluation and standardisation of mesenchymal stem cell culture conditions to generate conditioned medium favourable to cardiac c-kit cell growth
    Ng WH, Umar Fuaad MZ, Azmi SM, Leong YY, Yong YK, Ng AMH, et al.
    Cell Tissue Res, 2019 Feb;375(2):383-396.
    PMID: 30232595 DOI: 10.1007/s00441-018-2918-7
    Mesenchymal stem cells (MSCs) are known to secrete cardioprotective paracrine factors that can potentially activate endogenous cardiac c-kit cells (CCs). This study aims to optimise MSC growth conditions and medium formulation for generating the conditioned medium (CdM) to facilitate CC growth and expansion in vitro. The quality of MSC-CdM after optimisation of seeding density during MSC stabilisation and medium formulation used during MSC stimulation including glucose, ascorbic acid, serum and oxygen levels and the effects of treatment concentration and repeated CdM harvesting were assessed based on CC viability in vitro under growth factor- and serum-deprived condition. Our data showed that functional CdM can be produced from MSCs with a density of 20,000 cells/cm2, which were stimulated using high glucose (25 mM), ascorbic acid supplemented, serum-free medium under normoxic condition. The generated CdM, when applied to growth factor- and serum-deprived medium at 1:1 ratio, improved CC viability, migration and proliferation in vitro. Such an effect could further be augmented by generating CdM concentrates without compromising CC gene and protein expressions, while retaining its capability to undergo differentiation to form endothelial, smooth muscle and cardiomyocytes. Nevertheless, CdM could not be repeatedly harvested from the same MSC culture, as the protein content and its effect on CC viability deteriorated after the first harvest. In conclusion, this study provides a proof-of-concept strategy to standardise the production of CdM from MSCs based on rapid, stepwise assessment of CC viability, thus enabling production of CdM favourable to CC growth for in vitro or clinical applications.
    Matched MeSH terms: Myocytes, Cardiac/cytology; Myocytes, Cardiac/drug effects; Myocytes, Cardiac/metabolism
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