scholarly journals Scar Formation with Decreased Cardiac Function Following Ischemia/Reperfusion Injury in 1 Month Old Swine

2019 ◽  
Vol 7 (1) ◽  
pp. 1 ◽  
Author(s):  
Emma J Agnew ◽  
Nivedhitha Velayutham ◽  
Gabriela Matos Ortiz ◽  
Christina M Alfieri ◽  
Luis Hortells ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Mitotic Activity ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Myocardial Damage ◽  
Cardiac Regeneration ◽  
Scar Formation ◽  
Sham Operation ◽  
Large Mammals

Studies in mice show a brief neonatal period of cardiac regeneration with minimal scar formation, but less is known about reparative mechanisms in large mammals. A transient cardiac injury approach (ischemia/reperfusion, IR) was used in weaned postnatal day (P)30 pigs to assess regenerative repair in young large mammals at a stage when cardiomyocyte (CM) mitotic activity is still detected. Female and male P30 pigs were subjected to cardiac ischemia (1 h) by occlusion of the left anterior descending artery followed by reperfusion, or to a sham operation. Following IR, myocardial damage occurred, with cardiac ejection fraction significantly decreased 2 h post-ischemia. No improvement or worsening of cardiac function to the 4 week study end-point was observed. Histology demonstrated CM cell cycling, detectable by phospho-histone H3 staining, at 2 months of age in multinucleated CMs in both sham-operated and IR pigs. Inflammation and regional scar formation in the epicardial region proximal to injury were observed 4 weeks post-IR. Thus, pigs subjected to cardiac IR at P30 show myocardial damage with a prolonged decrease in cardiac function, formation of a regional scar, and increased inflammation, but do not regenerate myocardium even in the presence of CM mitotic activity.

scholarly journals SCAR FORMATION AND DECREASED CARDIAC FUNCTION FOLLOWING ISCHEMIA/REPERFUSION INJURY IN 1-MONTH-OLD SWINE

2019 ◽  
Author(s):  
Emma J Agnew ◽  
Nivedhitha Velayutham ◽  
Gabriela Matos Ortiz ◽  
Christina M Alfieri ◽  
Victoria Moore ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Myocardial Damage ◽  
Cardiac Regeneration ◽  
Scar Formation ◽  
Sham Operation ◽  
Large Mammals ◽  
Cell Cycling

ABSTRACTStudies in mice show a brief neonatal period of cardiac regeneration with minimal scar formation. Less is known about reparative mechanisms in large mammals. A transient cardiac injury approach (ischemia/reperfusion, IR) was used in weaned postnatal day (P)30 pigs, to assess regenerative repair in young large mammals. Female and male P30 pigs were subjected to cardiac ischemia (1 hour) by occlusion of the left anterior descending artery followed by reperfusion, or to sham operation. Following IR, myocardial damage occurred, with cardiac ejection fraction significantly decreased 2 hours post-ischemia. No improvement or worsening of cardiac function to the 4 week study end-point was observed. Histology demonstrated cardiomyocyte (CM) cell cycling at 2-months-of-age in multinucleated CMs in both sham-operated and IR pigs. Regional scar formation and inflammation in the epicardial region proximal to injury were observed 4 weeks post-IR. Sex differences were found, suggestive of females creating a greater fibrotic response with worse cardiac function, highlighting the importance of representing both sexes in cardiac injury studies. Together, our results describe an effective novel cardiac injury model in P30 swine, at a time when CMs are still cycling. Pigs subjected to IR show myocardial damage with a prolonged decrease in cardiac function, formation of a small, regional scar with increased inflammation. These data demonstrate that P30 pigs do not regenerate myocardium, even in the presence of CM mitotic activity, but form a scar after transient IR injury.NEW & NOTEWORTHYHere, we report for the first time ischemia/reperfusion (IR) cardiac injury in 1-month-old (P30) pigs. This model of IR injury highlights lack of cardiac regeneration, even in the presence of cardiomyocyte (CM) cell cycling in young swine. An effective injury approach is described for use in large mammals to investigate cardiac function, CM cell cycling, extracellular matrix (ECM) remodeling, and gene expression changes, while highlighting the importance of studying both sexes.

IKKβ inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury

2007 ◽  
Vol 293 (4) ◽  
pp. H2248-H2253 ◽  
Author(s):  
Nancy C. Moss ◽  
William E. Stansfield ◽  
Monte S. Willis ◽  
Ru-Hang Tang ◽  
Craig H. Selzman
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Myocardial Damage ◽  
Nuclear Factor Κb ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Artery Ligation ◽  
Cardiac Morbidity

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-κB (NF-κB) has been implicated as a key mediator of reperfusion injury. Activation of NF-κB is dependent upon the phosphorylation of its inhibitor, IκBα, by the specific inhibitory κB kinase (IKK) subunit, IKKβ. We hypothesized that specific antagonism of the NF-κB inflammatory pathway through IKKβ inhibition reduces acute myocardial damage following IR injury. C57BL/6 mice underwent left anterior descending (LAD) artery ligation and release in an experimental model of acute IR. Bay 65-1942, an ATP-competitive inhibitor that selectively targets IKKβ kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKKβ inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKKβ inhibition. These findings were further associated with decreased expression of phosphorylated IκBα and phosphorylated p65 in myocardial tissue. In addition, IKKβ inhibition decreased serum levels of TNF-α and IL-6, two prototypical downstream effectors of NF-κB activity. These results demonstrate that specific IKKβ inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.

scholarly journals Cardioprotective Effect of Betulinic Acid on Myocardial Ischemia Reperfusion Injury in Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Anzhou Xia ◽  
Zhi Xue ◽  
Yong Li ◽  
Wei Wang ◽  
Jieyun Xia ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
Betulinic Acid ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tunel Assay ◽  
Sham Operation ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Objectives. This study aims to investigate the effect of betulinic acid (BA) on myocardial ischemia reperfusion/injury in an open-chest anesthetized rat model.Methods. The model was induced by 30 minutes left anterior descending occlusion followed by 2 hours reperfusion. There are six groups in our present study: sham operation group, ischemia/reperfusion group, low-dosage BA group, medium-dosage BA group, high-dosage BA group, and fosinopril sodium group. Rats in the latter four groups were administrated with BA (50, 100, and 200 mg/kg, i.g.) or fosinopril sodium (10 mg/kg, i.g.) once a day for 7 days before operation, respectively. Rats in the former two groups were given the same volume of vehicle (0.5% CMC-Na, i.g.). During the operation, cardiac function was continuously monitored. Serum LDH and CK were measured with colorimetric assays. The expression of Bcl-2 and Bax and the apoptosis of cardiomyocytes were investigated with western blot and TUNEL assay, respectively.Results. Pretreatment with BA improved cardiac function and attenuated LDH and CK activities compared with IR group. Further investigation demonstrated that the expression of Bcl-2 and Bax and TUNEL assay was in line with the above results.Conclusion. BA may reduce the release of LDH and CK, prevent cardiomyocytes apoptosis, and eventually alleviate the extent of the myocardial ischemia/reperfusion injury.

scholarly journals Effects of propofol on cardiac function and miR-494 expression in rats with hepatic ischemia/reperfusion injury

2021 ◽  
Vol 49 (3) ◽  
pp. 030006052199098
Author(s):  
Jie Lv ◽  
Xiaohua Zou ◽  
Chao Yu ◽  
Wei Ou ◽  
Chengyi Sun
Keyword(s):  
Cardiac Function ◽  
Group Treatment ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Sham Operation ◽  
Myocardial Cells ◽  
Hepatic Ischemia ◽  
Sham Operation Group ◽  
Hepatic Ischemia Reperfusion

Objective This study aimed to investigate the effects of propofol on cardiac function and miR-494 expression in rats with hepatic ischemia/reperfusion (I/R) injury. Methods Forty healthy adult male Sprague-Dawley rats were allocated to the sham operation group and three hepatic I/R injury groups. The I/R injury groups included I/R injury only (I/R group), treatment with propofol (propofol group), and treatment with propofol + overexpressed miR-494 (propofol+miR-494 group). Apoptosis of myocardial cells and changes in cardiac function indices, including left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and left ventricular posterior wall thickness, as well as changes in miR-494, were monitored. Results The apoptotic rate of myocardial cells in the I/R group was higher, cardiac function was deteriorated, and miR-494 levels were elevated compared with the sham group. The apoptotic rate was lower, cardiac function was improved, and miR-494 levels were suppressed in the propofol group compared with the I/R group. The apoptotic rate was higher, cardiac function was deteriorated, and miR-494 levels were elevated in the propofol+miR-494 group compared with the propofol group. Conclusion Propofol plays a vital role in preventing myocardial cell apoptosis and improvement of cardiac function by suppressing miR-494 in a hepatic I/R injury rat model.

Abstract 299: Cardioprotection from Ischemia/Reperfusion Injury by β-Arrestin-Biased β2-Adrenergic Receptor Activation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Laurel A Grisanti ◽  
Claudio de Lucia ◽  
Erhe Gao ◽  
Walter J Koch ◽  
Jeffrey L Benovic ◽  
...  
Keyword(s):  
Cell Death ◽  
Cardiac Function ◽  
Infarct Size ◽  
Adrenergic Receptor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Receptor Activation ◽  
Tunel Staining ◽  
Intracellular Loop

β-Adrenergic receptors (βAR) are important regulators of cardiac function in the normal and failing heart. Activation of the β1AR subtype increases contractility and cardiomyocyte death whereas the β2AR can promote survival. In response to cardiac injury, increased catecholamines activate and downregulate β1AR thus, β-adrenergic receptor antagonists or β-blockers are commonly prescribed in to restore β1AR expression and preserve contractility. However, promoting the pro-survival effects of β2AR, which are known to occur in part through β-arrestin (ARR)-dependent signaling, may be a beneficial therapeutic strategy. Pepducins have been developed based on the intracellular loop (ICL) domains of β2AR to activate either Gαs- or βARR-dependent β2AR signaling pathways. We hypothesized that pepducin-mediated engagement of βARR-dependent β2AR signaling in the heart would be therapeutically advantageous following ischemia/reperfusion (I/R) injury. To test this, wild-type (WT) C57BL/6 mice received three intracardiac injections of either a βARR-biased pepducin (ICL1-9) or a scrambled control pepducin at the time of ischemia (30 min) followed by reperfusion. Assessment of cardiomyocyte death 24h post-I/R using TUNEL staining showed a decrease in cell death in animals treated with ICL1-9 when compared to scrambled pepducin, correlating with decreased infarct size and improved cardiac function as measured by echocardiography. Assessment of cardiac function at later time points showed that the cardioprotective effects of ICL1-9 were preserved over time and resulted in decreased cardiac remodeling. Although βARR1KO mice displayed similar cell death, infarct size, and contractility changes following I/R as their WT counterparts, they did not manifest a cardioprotective response from ICL1-9 treatment, indicating that βARR signaling is essential in relaying ICL1-9-dependent cardioprotection. These results demonstrate that pharmacologically-mediated activation of βARR-biased β2AR signaling provides a therapeutic benefit in the context of I/R-induced injury and may provide an improved strategy for the treatment of acute cardiac injury.

scholarly journals The Diverse Roles of TNNI3K in Cardiac Disease and Potential for Treatment

2021 ◽  
Vol 22 (12) ◽  
pp. 6422
Author(s):  
Caroline Pham ◽  
Noelia Muñoz-Martín ◽  
Elisabeth M. Lodder
Keyword(s):  
Cardiac Disease ◽  
Genetic Variants ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Regeneration ◽  
Cardiac Diseases ◽  
Supraventricular Arrhythmias ◽  
Clinical Perspective ◽  
Physiological Processes

In the two decades since the discovery of TNNI3K it has been implicated in multiple cardiac phenotypes and physiological processes. TNNI3K is an understudied kinase, which is mainly expressed in the heart. Human genetic variants in TNNI3K are associated with supraventricular arrhythmias, conduction disease, and cardiomyopathy. Furthermore, studies in mice implicate the gene in cardiac hypertrophy, cardiac regeneration, and recovery after ischemia/reperfusion injury. Several new papers on TNNI3K have been published since the last overview, broadening the clinical perspective of TNNI3K variants and our understanding of the underlying molecular biology. We here provide an overview of the role of TNNI3K in cardiomyopathy and arrhythmia covering both a clinical perspective and basic science advancements. In addition, we review the potential of TNNI3K as a target for clinical treatments in different cardiac diseases.

Overexpression of miR-431 attenuates hypoxia/reoxygenation-induced myocardial damage via autophagy-related 3

2020 ◽  
Author(s):  
Kang Zhou ◽  
Yan Xu ◽  
Qiong Wang ◽  
Lini Dong
Keyword(s):  
Cell Viability ◽  
Cell Apoptosis ◽  
Myocardial Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Protective Role ◽  
Human Cardiomyocytes ◽  
Hypoxia Reoxygenation

Abstract Myocardial injury is still a serious condition damaging the public health. Clinically, myocardial injury often leads to cardiac dysfunction and, in severe cases, death. Reperfusion of the ischemic myocardial tissues can minimize acute myocardial infarction (AMI)-induced damage. MicroRNAs are commonly recognized in diverse diseases and are often involved in the development of myocardial ischemia/reperfusion injury. However, the role of miR-431 remains unclear in myocardial injury. In this study, we investigated the underlying mechanisms of miR-431 in the cell apoptosis and autophagy of human cardiomyocytes in hypoxia/reoxygenation (H/R). H/R treatment reduced cell viability, promoted cell apoptotic rate, and down-regulated the expression of miR-431 in human cardiomyocytes. The down-regulation of miR-431 by its inhibitor reduced cell viability and induced cell apoptosis in the human cardiomyocytes. Moreover, miR-431 down-regulated the expression of autophagy-related 3 (ATG3) via targeting the 3ʹ-untranslated region of ATG3. Up-regulated expression of ATG3 by pcDNA3.1-ATG3 reversed the protective role of the overexpression of miR-431 on cell viability and cell apoptosis in H/R-treated human cardiomyocytes. More importantly, H/R treatments promoted autophagy in the human cardiomyocytes, and this effect was greatly alleviated via miR-431-mimic transfection. Our results suggested that miR-431 overexpression attenuated the H/R-induced myocardial damage at least partly through regulating the expression of ATG3.

Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart

2013 ◽  
Vol 305 (4) ◽  
pp. H542-H550 ◽  
Author(s):  
Toshihiro Shinbo ◽  
Kenichi Kokubo ◽  
Yuri Sato ◽  
Shintaro Hagiri ◽  
Ryuji Hataishi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Left Ventricular ◽  
Hydrogen Gas ◽  
Coronary Artery Ligation

Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H2 is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H2 (2%), or NO + H2, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H2 alone. NO inhalation plus H2 reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H2 with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H2. In conclusion, breathing NO + H2 during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H2 gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.

Abstract 428: Pharmacologic and Activated Fibroblast-specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Joshua G Travers ◽  
Fadia A Kamal ◽  
Michelle L Nieman ◽  
Michelle A Sargent ◽  
Jeffery D Molkentin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
G Protein ◽  
Knockout Mice ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Ventricular Compliance

Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transform to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately the pathologic activation of G protein-coupled receptor kinase 2 (GRK2). We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast activation and cardiac remodeling. To investigate this hypothesis, mice were subjected to ischemia/reperfusion (I/R) injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein. While animals receiving vehicle demonstrated a reduction in overall cardiac function as measured by echocardiography, mice treated with gallein exhibited nearly complete preservation of cardiac function and reduced fibrotic scar formation. We next sought to establish the cell specificity of this compound by treating inducible cardiomyocyte- and activated fibroblast-specific GRK2 knockout mice post-I/R. Although we observed modest restoration in cardiac function in cardiomyocyte-specific GRK2 null mice, treatment of these mice with gallein resulted in further protection against myocardial dysfunction following injury, suggesting a functional role in other cardiac cell types, including fibroblasts. Activated fibroblast-specific GRK2 knockout mice were also subjected to ischemia/reperfusion injury; these animals displayed preserved myocardial function and reduced collagen deposition compared to littermate controls following injury. Furthermore, systemic Gβγ-GRK2 inhibition by gallein did not appear to confer further protection over activated fibroblast-specific GRK2 ablation alone. In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression.

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