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

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.

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Abstract 270: Microsomal Prostaglandin E Synthase-1 and Endothelial EP4 Receptor Reduces Myocardial Ischemia-reperfusion Injury via Improving Microcirculatory Perfusion

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.38.suppl_1.270 ◽

2018 ◽

Vol 38 (Suppl_1) ◽

Author(s):

Liyuan Zhu ◽

Chuansheng Xu ◽

Huifeng Hao ◽

Sheng Hu ◽

Qing Wan ◽

...

Keyword(s):

Myocardial Ischemia ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Prostaglandin E ◽

Microcirculatory Perfusion ◽

Prostaglandin E Synthase ◽

Ep4 Receptor ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00553.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. H1723-H1741 ◽

Cited By ~ 194

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.

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

Circulation Research ◽

10.1161/res.119.suppl_1.61 ◽

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.

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Prevention of Cerebral Oxidative Injury by Post-ischemic Intravenous Administration of Shengmai San

The American Journal of Chinese Medicine ◽

10.1142/s0192415x06004120 ◽

2006 ◽

Vol 34 (04) ◽

pp. 591-600 ◽

Cited By ~ 27

Author(s):

Haruyo Ichikawa ◽

Lei Wang ◽

Tetsuya Konishi

Keyword(s):

Cerebral Ischemia ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Heart Diseases ◽

Ischemia Reperfusion ◽

Oxidative Injury ◽

Protein Carbonyl ◽

Thiobarbituric Acid Reactive Substance ◽

Cerebral Ischemia Reperfusion ◽

Shengmai San

Shengmai San (SMS) is a traditional Chinese medicine (TCM) comprising three different herbal components, Panax ginseng, Ohiopogon japonicus and Fructus schisandrae and has been used for treating coronary heart diseases (Bensky and Barolet, 1990). It was shown that SMS effectively prevented cerebral oxidative injury in rats when it administered into the duodenum before cerebral ischemia-reperfusion. In the present study, we examined whether post-ischemic administration of SMS can ameliorate cerebral ischemia-reperfusion injury in rats as well. Results showed that SMS injected immediately after ischemia also prevented the ischemia-reperfusion injury, when the effect was evaluated by the formation of protein carbonyl and thiobarbituric acid reactive substance (TBARS), and the loss of glutathione peroxidase (GPX). The preventative potential of SMS was decreased rapidly dependent on the time lag until SMS was injected after ischemia. However, it was noted that intravenously administered SMS protected the oxidative injury approximately 30% even after 60 min of reperfusion in terms of protein carbonyl formation. It is thus suggested that SMS injection might be useful for preventing the progression of injury in cerebral infarction after stroke.

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Ischemia/reperfusion injury is increased and cardioprotection by a postconditioning protocol is lost as cardiac hypertrophy develops in nandrolone treated rats

Basic Research in Cardiology ◽

10.1007/s00395-010-0143-y ◽

2010 ◽

Vol 106 (3) ◽

pp. 409-420 ◽

Cited By ~ 33

Author(s):

C. Penna ◽

F. Tullio ◽

M.-G. Perrelli ◽

F. Moro ◽

G. Abbadessa ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion

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Evaluating Novel Targets of Ischemia Reperfusion Injury in Pig Models

International Journal of Molecular Sciences ◽

10.3390/ijms20194749 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4749 ◽

Cited By ~ 4

Author(s):

Andrea Baehr ◽

Nikolai Klymiuk ◽

Christian Kupatt

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Heart Diseases ◽

Health Care Systems ◽

Ischemia Reperfusion ◽

Developed Countries ◽

Predictive Capacity ◽

Coronary Heart Diseases ◽

Care Systems ◽

Clinical Experiments

Coronary heart diseases are of high relevance for health care systems in developed countries regarding patient numbers and costs. Disappointingly, the enormous effort put into the development of innovative therapies and the high numbers of clinical studies conducted are counteracted by the low numbers of therapies that become clinically effective. Evidently, pre-clinical research in its present form does not appear informative of the performance of treatments in the clinic and, even more relevant, it appears that there is hardly any consent about how to improve the predictive capacity of pre-clinical experiments. According to the steadily increasing relevance that pig models have gained in biomedical research in the recent past, we anticipate that research in pigs can be highly predictive for ischemia-reperfusion injury (IRI) therapies as well. Thus, we here describe the significance of pig models in IRI, give an overview about recent developments in evaluating such models by clinically relevant methods and present the latest insight into therapies applied to pigs under IRI.

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Abstract 204: Modification of AIFm2 By 4HNE Leads to Retrograde Stress Signaling During Ischemia- Reperfusion Injury in Heart

Circulation Research ◽

10.1161/res.127.suppl_1.204 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Sudha Sharma ◽

Susmita Bhattarai ◽

Utsab Subedi ◽

Christina Acosta ◽

Hosne Ara ◽

...

Keyword(s):

Protein Expression ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Adaptor Protein ◽

Ischemic Heart ◽

Spectrometric Analysis ◽

Apoptosis Inducing Factor ◽

First Time

Myocardial infarction is a leading cause of death worldwide and occurs due to blockage in blood supply to the heart. Re-establishment of blood flow after a brief period of ischemia leads to paradoxical exacerbation of the cardiomyocyte and its death. This phenomenon is known as ischemia-reperfusion injury. Major evidence in the pathogenesis of ischemia-reperfusion injury is due to oxidative stress, which is an imbalance between reactive oxygen species (ROS) and antioxidants. Membrane consisting of polyunsaturated fatty acid is attacked by ROS leading to lipid peroxidation and the generation of one of the toxic aldehydes 4-hydroxynonenal (4-HNE). Evidence suggests that 4-HNE increases during an ischemia-reperfusion injury in the heart. Apoptosis-inducing factor, mitochondrion-associated 2 (AIFM2) is a mitochondrial located oxidoreductase that participates in caspase-independent apoptosis. In this study, we sought to identify the role of 4-HNE in regulating AIFm2 translocation and cardiomyocyte death during an ischemia-reperfusion injury in the heart. Following ischemia both RNA and protein expression of AIFm2 significantly increased in the ischemic heart compared to sham. Also, 4-HNE adducted AIFm2 translocated from mitochondria to the nucleus shown by western blot analysis in ischemic heart. The mass spectrometric analysis was done to see the modification site on AIFm2 by 4-HNE and revealed that His 174 and Cys 187 are two sites on AIFm2 where 4-HNE adduction occurred. To identify the modification site responsible for AIFm2 translocation we performed site-direct mutagenesis in H9C2 cardiomyocyte, where Histidine 174 was replaced by arginine and Cys 187 was replaced by threonine. When the ischemia-reperfusion injury was induced, only Histidine 174 mutant failed to translocate to the nucleus indicating His 174 modification by 4-HNE was responsible for AIFm2 translocation. To further support the transport mechanism, protein expression of Importin; an adaptor protein responsible for the transfer of proteins to the nucleus was increased in the ischemic heart compared to sham. Collectively, those results for the first time identify the unique role of 4-HNE modification on AIFm2 protein during an ischemia-reperfusion injury in the heart.

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