scholarly journals The roles of long noncoding RNAs in myocardial pathophysiology

2019 ◽  
Vol 39 (11) ◽  
Author(s):  
Cheng Chen ◽  
Yuting Tang ◽  
Hui Sun ◽  
Xiaofang Lin ◽  
Bimei Jiang
Keyword(s):  
Structural Changes ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Current Knowledge ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Noncoding Rnas ◽  
Cardiac Cells ◽  
Long Noncoding Rnas ◽  
Ischemic Heart

Abstract Long noncoding RNAs (lncRNAs), more than 200 nt in length, are functional molecules found in various species. These lncRNAs play a vital role in cell proliferation, differentiation, and degeneration and are also involved in pathophysiological processes of cancer and neurodegenerative, autoimmune, and cardiovascular diseases (CVDs). In recent years, emerging challenges for intervention studies on ischemic heart diseases have received much attention. LncRNAs have a key function in the alleviation of myocardial infarction (MI) injury and myocardial ischemia–reperfusion injury. During cardiac hypertrophy (CH) and fibrosis, cardiac cells undergo structural changes and become dysfunctional due to the effects of neurohormonal factors. LncRNAs may serve as important therapeutic targets that promote cardiac remodeling and then retard the development of heart failure (HF). In addition, studies on the roles and mechanisms of action of lncRNAs participating in cardiac pathophysiology via other factors have become the focus of research worldwide. Here, we review the current knowledge on various lncRNAs and their functions in cardiac biology, particularly concentrating on ischemic heart disease, CH, and cardiac fibrosis. We next discuss the predictive value of lncRNAs as diagnostic biomarkers of CVDs.

Abstract 61: Ablation of BK Ca Channels Results in Cardiac Hypertrophy

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Harpreet Singh ◽  
Kajol Shah ◽  
Devsena Ponnalagu ◽  
Sanjay Chandrasekhar ◽  
Andrew R Kohut ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Structural Changes ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Interventricular Septum ◽  
Wild Type

Expression and activation of the large conductance calcium and voltage-gated potassium (BK Ca ) channels encoded by Kcnma1 gene is shown to be vital in cardioprotection from ischemia-reperfusion injury. BK Ca channels present in SA node cells regulate the heart rate, and in blood vessels play an active role in vascular relaxation. However, the role of BK Ca in regulation of structure and function of the heart is not fully-established. Using Kcnma1 -/- mice, we have observed structural changes in cardiomyocytes and compromised cardiac function as compared to wild type mice. Absence of BK Ca resulted in significant increase in size of adult cardiomyocytes (from 7.95 + 0.1 um 2 to 9.68 + 0.1 um 2 , p < 0.01, n=480 cells each) and also increased cardiac fibrosis. Further to determine underlying signaling mechanisms in cardiac hypertrophy, we performed microarray analysis of RNAs isolated from wild type and Kcnma1 -/- mice (n=3) hearts. We found up regulation of a class of cardiac hypertrophy markers (myosin variants) and changes in the expression of several mitochondrial genes (such as ND4) directly associated with heart diseases in Kcnma1 -/- mice. To evaluate the functional consequence of absence of BK Ca , we performed high-resolution echocardiography on wild type and Kcnma1 -/- mice. Under anesthesia (1.5% isoflurane), left ventricle of Kcnma1 -/- mice showed significant reduction (p < 0.05) in ejection fraction (56 + 2 %, n=7) as compared to wild type (74 + 3 %, n=6) as well as fractional shortening (23 + 3 %, n=7, and 39 + 3 %, n=6, respectively). Similarly, right ventricle had a lower ejection fraction (35.7 + 4% vs 56.9 + 5 %, n > 5) in Kcnma1 -/- as compared to wild type mice. In agreement with our histopathology and microarray data, Kcnma1 -/- mice showed increased posterior wall thickness (0.75 + 0.3 mm vs 0.62 + 0.1 mm) and interventricular septum thickness (0.83 + 0.4 mm, n=7 vs 0.68 + 0.3 mm, n=6) . Together, these data imply that BK Ca plays a direct role in cardiac hypertrophy and cardiac function.

scholarly journals Multidimensional Regulation of Cardiac Mitochondrial Potassium Channels

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1554
Author(s):  
Bogusz Kulawiak ◽  
Piotr Bednarczyk ◽  
Adam Szewczyk
Keyword(s):  
Potassium Channels ◽  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Current Knowledge ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Cardiac Cells ◽  
Cardiac Ischemia ◽  
Inner Mitochondrial Membrane

Mitochondria play a fundamental role in the energetics of cardiac cells. Moreover, mitochondria are involved in cardiac ischemia/reperfusion injury by opening the mitochondrial permeability transition pore which is the major cause of cell death. The preservation of mitochondrial function is an essential component of the cardioprotective mechanism. The involvement of mitochondrial K+ transport in this complex phenomenon seems to be well established. Several mitochondrial K+ channels in the inner mitochondrial membrane, such as ATP-sensitive, voltage-regulated, calcium-activated and Na+-activated channels, have been discovered. This obliges us to ask the following question: why is the simple potassium ion influx process carried out by several different mitochondrial potassium channels? In this review, we summarize the current knowledge of both the properties of mitochondrial potassium channels in cardiac mitochondria and the current understanding of their multidimensional functional role. We also critically summarize the pharmacological modulation of these proteins within the context of cardiac ischemia/reperfusion injury and cardioprotection.

Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures

2011 ◽  
Vol 301 (5) ◽  
pp. H1723-H1741 ◽  
Author(s):  
Shoji Sanada ◽  
Issei Komuro ◽  
Masafumi Kitakaze
Keyword(s):  
Reperfusion Injury ◽  
Clinical Evidence ◽  
Clinical Medicine ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Developed Countries ◽  
Adverse Outcomes ◽  
Ischemic Heart ◽  
Pathophysiological Mechanism

Heart diseases due to myocardial ischemia, such as myocardial infarction or ischemic heart failure, are major causes of death in developed countries, and their number is unfortunately still growing. Preliminary exploration into the pathophysiology of ischemia-reperfusion injury, together with the accumulation of clinical evidence, led to the discovery of ischemic preconditioning, which has been the main hypothesis for over three decades for how ischemia-reperfusion injury can be attenuated. The subcellular pathophysiological mechanism of ischemia-reperfusion injury and preconditioning-induced cardioprotection is not well understood, but extensive research into components, including autacoids, ion channels, receptors, subcellular signaling cascades, and mitochondrial modulators, as well as strategies for modulating these components, has made evolutional progress. Owing to the accumulation of both basic and clinical evidence, the idea of ischemic postconditioning with a cardioprotective potential has been discovered and established, making it possible to apply this knowledge in the clinical setting after ischemia-reperfusion insult. Another a great outcome has been the launch of translational studies that apply basic findings for manipulating ischemia-reperfusion injury into practical clinical treatments against ischemic heart diseases. In this review, we discuss the current findings regarding the fundamental pathophysiological mechanisms of ischemia-reperfusion injury, the associated protective mechanisms of ischemic pre- and postconditioning, and the potential seeds for molecular, pharmacological, or mechanical treatments against ischemia-reperfusion injury, as well as subsequent adverse outcomes by modulation of subcellular signaling mechanisms (especially mitochondrial function). We also review emerging translational clinical trials and the subsistent clinical comorbidities that need to be overcome to make these trials applicable in clinical medicine.

scholarly journals Role of Higenamine in Heart Diseases: A Mini-Review

2022 ◽  
Vol 12 ◽  
Author(s):  
Jianxia Wen ◽  
Mingjie Li ◽  
Wenwen Zhang ◽  
Haoyu Wang ◽  
Yan Bai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Heart Disease ◽  
Reperfusion Injury ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia

Higenamine, a natural product with multiple targets in heart diseases, is originally derived from Aconitum, which has been traditionally used in China for the treatment of heart disease, including heart failure, arrhythmia, bradycardia, cardiac ischemia/reperfusion injury, cardiac fibrosis, etc. This study is aimed to clarify the role of higenamine in heart diseases. Higenamine has effects on improving energy metabolism of cardiomyocytes, anti-cardiac fibroblast activation, anti-oxidative stress and anti-apoptosis. Accumulating evidence from various studies has shown that higenamine exerts a wide range of cardiovascular pharmacological effects in vivo and in vitro, including alleviating heart failure, reducing cardiac ischemia/reperfusion injury, attenuating pathological cardiac fibrosis and dysfunction. In addition, several clinical studies have reported that higenamine could continuously increase the heart rate levels of healthy volunteers as well as patients with heart disease, but there are variable effects on systolic blood pressure and diastolic blood pressure. Moreover, the heart protection and therapeutic effects of higenamine on heart disease are related to regulating LKB1/AMPKα/Sirt1, mediating the β2-AR/PI3K/AKT cascade, induction of heme oxygenase-1, suppressing TGF-β1/Smad signaling, and targeting ASK1/MAPK (ERK, P38)/NF-kB signaling pathway. However, the interventional effects of higenamine on heart disease and its underlying mechanisms based on experimental studies have not yet been systematically reviewed. This paper reviewed the potential pharmacological mechanisms of higenamine on the prevention, treatment, and diagnosis of heart disease and clarified its clinical applications. The literature shows that higenamine may have a potent effect on complex heart diseases, and proves the profound medicinal value of higenamine in heart disease.

scholarly journals Prostaglandin E Receptor Subtype 4 Signaling in the Heart: Role in Ischemia/Reperfusion Injury and Cardiac Hypertrophy

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Lei Pang ◽  
Yin Cai ◽  
Eva Hoi Ching Tang ◽  
Michael G. Irwin ◽  
Haichun Ma ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Prostaglandin E ◽  
Ischemic Heart Diseases ◽  
Ep4 Receptor ◽  
Arachidonic Acids

Prostaglandin E2(PGE2) is an endogenous lipid mediator, produced from the metabolism of arachidonic acids, upon the sequential actions of phospholipase A2, cyclooxygenases, and prostaglandin E synthases. The various biological functions governed by PGE2are mediated through its four distinct prostaglandin E receptors (EPs), designated as EP1, EP2, EP3, and EP4, among which the EP4 receptor is the one most widely distributed in the heart. The availability of global or cardiac-specific EP4 knockout mice and the development of selective EP4 agonists/antagonists have provided substantial evidence to support the role of EP4 receptor in the heart. However, like any good drama, activation of PGE2-EP4 signaling exerts both protective and detrimental effects in the ischemic heart disease. Thus, the primary object of this review is to provide a comprehensive overview of the current progress of the PGE2-EP4 signaling in ischemic heart diseases, including cardiac hypertrophy and myocardial ischemia/reperfusion injury. A better understanding of PGE2-EP4 signaling should promote the development of more effective therapeutic approaches to treat the ischemic heart diseases without triggering unwanted side effects.

scholarly journals Octreotide (somatostatin analog) attenuates cardiac ischemia/reperfusion injury via activating nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway in rat model of hyperthyroidism

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Randa Salah Gomaa ◽  
Nevertyty Mohamed Mahmoud ◽  
Nourelhuda Abdelaziz Mohammed
Keyword(s):  
Cardiac Tissue ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Treated Group ◽  
Ischemic Heart ◽  
Gene Expressions ◽  
Rat Hearts ◽  
Nrf2 Signaling Pathway ◽  
Cardiac Hemodynamics

Abstract Background Hyperthyroidism is known to increase the risk of ischemic heart diseases. Octreotide has been reported to attenuate ischemia/reperfusion (I/R) injury. Whether it is useful when ischemic heart disease is accompanied with co-morbidities like hyperthyroidism needs more clarifying. So, this study aimed to explore the effect of octreotide on cardiac I/R injury in hyperthyroid rats and to clarify if Nrf2 activation is involved in this effect. Forty adult female Wistar rats were subdivided into control (euthyroid) (n = 10) and hyperthyroid (n = 30) groups. Rats in hyperthyroid group received l-thyroxine (12 mg/L) in drinking water for 35 days, then were randomly divided into three equal subgroups (n = 10): hyperthyroid control positive group, hyperthyroid octreotide treated group, and hyperthyroid octreotide + Nrf2 inhibitor (brusatol) treated group. Isolated hearts were submitted to I/R and evaluated for cardiac hemodynamics and infarct size. Serum T3 and T4, coronary efflux lactate dehydrogenase (LDH) and creatine kinase-myoglobin binding (CK-MB) and cardiac tissue malondialdehyde (MDA) were estimated. Nrf2- regulated gene expressions of HO-1, SOD, GPx, and catalase were assessed. Results Octreotide administration to hyperthyroid rats improved baseline and post-ischemic recovery of cardiac hemodynamics, decreased the high coronary efflux LDH and CK-MB and tissue MDA, reduced infarction size, and upregulated the decreased antioxidative enzymes HO-1, SOD, GPx, and catalase mRNA expressions in the hyperthyroid I/R rat hearts. The Nrf2 inhibitor brusatol reversed the cardioprotective effect of octreotide in hyperthyroid I/R rat hearts. Conclusion Octreotide can reduce oxidative stress to effectively alleviate I/R injury in the hyperthyroid rat hearts through upregulation of Nrf2-dependent antioxidative signaling pathways.

scholarly journals Suppressing Pyroptosis Augments Post-Transplant Survival of Stem Cells and Cardiac Function Following Ischemic Injury

2021 ◽  
Vol 22 (15) ◽  
pp. 7946
Author(s):  
Chang Youn Lee ◽  
Seahyoung Lee ◽  
Seongtae Jeong ◽  
Jiyun Lee ◽  
Hyang-Hee Seo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Stem Cell ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion ◽  
Cardiac Cells ◽  
Transplant Survival ◽  
Post Transplant ◽  
Heart Functions ◽  
Cell Death Mechanisms

The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1b production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.

scholarly journals Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia

2008 ◽  
Vol 294 (6) ◽  
pp. H2889-H2897 ◽  
Author(s):  
Qianwen Wang ◽  
Rajakumar V. Donthi ◽  
Jianxun Wang ◽  
Alex J. Lange ◽  
Lewis J. Watson ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
Cardiac Metabolism ◽  
Heart Weight ◽  
Acid Oxidation ◽  
Important Regulator

During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.

Abstract 782: Fra2 Mediates Oxygen-induced TGFbeta-1 mRNA Expression In Adult Cardiac Fibroblasts: Significance In Myocardial Fibrosis Following Ischemia-reperfusion Injury

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Sashwati Roy ◽  
Savita Khanna ◽  
Chandan K Sen
Keyword(s):  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Ischemia Reperfusion Injury ◽  
Cardiac Fibroblasts ◽  
Ischemia Reperfusion ◽  
Luciferase Reporter ◽  
Mrna Levels

Background . Transforming growth factor beta-1 (TGFbeta-1) is a key cytokine implicated in the development of cardiac fibrosis following ischemia-reperfusion (IR) injury. The profibrotic effects of TGFbeta-1 are primarily attributable to the differentiation of cardiac fibroblasts (CF) to myofibroblasts. Previously, we have reported perceived hyperoxia (Circ Res 92:264 –71), sub-lethal reoxygenation shock during IR, induces differentiation of CF to myofibroblasts at the infarct site. The mechanisms underlying oxygen-sensitive induction of TGFbeta-1 mRNA remain to be characterized. Hypothesis . Fra2 mediates oxygen-induced TGFbeta-1 mRNA expression in adult cardiac fibroblasts. Methods. TGFbeta-1 mRNA expression in infarct tissue was investigated in an IR injury model. The left anterior descending coronary artery of mice was transiently occluded for 60 minutes followed by reperfusion to induce IR injury. Spatially resolved infarct and non-infarct tissues were collected at 0, 1, 3, 5, and 7 days post-IR using laser capture microdissection. TGFbeta-1 mRNA levels were measured using real-time PCR. To investigate the role of oxygen in the regulation of TGFbeta-1, we used our previously reported model of perceived hyperoxia where CF (from 5wks old mice) after isolation were cultured at 5%O 2 (physiological pO 2 ) followed by transferring them to 20%O 2 to induce hyperoxic insult. Results & Conclusions. In vivo, a significant increase (p<0.01; n=5) in TGFbeta-1 mRNA was observed at the infarct site already at day 1 post-IR. The levels continued to increase until day 7 post-IR. In vitro, exposure of CF to 20%O 2 hyperoxic insult induced TGFbeta-1 mRNA (p<0.001; n=4) and protein (p<0.01; n=4) expression. Using a TGFbeta-1 promoter-luciferase reporter and DNA binding assays, we collected first evidence that AP-1 and its component Fra2 as major mediators of oxygen-induced TGFbeta-1 expression. Exposure to 20%O 2 resulted in increased localization of Fra2 in nucleus. siRNA-dependent Fra-2 knock-down completely abrogated oxygen-induced TGFbeta1 expression. In conclusion, this study presents first evidence that Fra-2 is involved in inducible TGFbeta1 expression in CF. Fra2 was noted as being central in regulating oxygen-induced TGFbeta-1 expression.s

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