Abstract 54: Probenecid Improves Myocardial Function in an Ischemic Heart Disease Murine Model

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Nathan Robbins ◽  
Sheryl E Koch ◽  
Min Jiang ◽  
Michael Tranter ◽  
Xiaoping Ren ◽  
...  
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Infarct Size ◽  
Cell Viability ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Transient Receptor Potential Vanilloid ◽  
High Concentrations

Introduction Probenecid, previously used for the treatment of gout, is a transient receptor potential vanilloid 2 (TRPV2) agonist. We have found TRPV2 in murine cardiomyocytes and when stimulated by probenecid, results in a positive inotropic response through Ca 2+ influx independent of β-adrenergic signaling. Our hypothesis is that probenecid will increase contractility without affecting cell survival. Methods We studied the role of probenecid as a positive inotrope in a mouse model of ischemic heart disease. We administered probenecid via intraperitoneal injections (100mg/kg) before and after ischemia/reperfusion injury (I/R) and orally via treated water (100mg/kg daily for 4 weeks), using saline injections and untreated water as respective controls. Ischemia was induced by a 45 minute ligation of the LAD followed by reperfusion and all mice were followed serially via echocardiography. We also evaluated the effects of probenecid on HL-1 cell apoptosis by conducting cell viability assays. Results Treatment with probenecid before I/R had no effect on subsequent infarct size (51.6±3.71% vs. 53.4±1.54%;P=NS). However, post-I/R probenecid caused an increase in ejection fraction (EF) of 10.9±1.98% in mice with initial EF between 40-50% (n=6; P<0.01) and 7.28±1.63% in mice with higher initial EF (50-60%) (n=6; p<0.01). Echocardiographic analysis of mice with oral probenecid after I/R demonstrated higher EF and smaller diastolic volume (47.19±2.29%; 79.57mL±1.63; n=6) compared to untreated mice (43.67±2.91%; 89.05mL±5.67; n=6). Cell viability assays showed high concentrations of probenecid had minimal effect on cell viability (88.6±6.2% of control) whereas treatment with high concentrations of isoproterenol (10mM) greatly decreased cell viability (6.7±0.1% of control). Conclusions These experiments demonstrate 1) probenecid increases myocardial contractility at baseline and significantly more so after I/R injury; 2) probenecid therapy improves function when used chronically; 3) the increase in contractility is not associated with either increased infarct size in vivo or apoptosis in vitro. Thus, unlike other positive inotropes, such as isoproterenol, probenecid increases contractility without resulting in significant cell death.

Repeated intermittent stress exacerbates myocardial ischemia-reperfusion injury

1998 ◽  
Vol 274 (2) ◽  
pp. R470-R475 ◽  
Author(s):  
Deborah A. Scheuer ◽  
Steven W. Mifflin
Keyword(s):  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Infarct Size ◽  
Chronic Stress ◽  
Restraint Stress ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Chronic stress in humans has been correlated with increased risk for ischemic heart disease. Thus experiments were conducted to determine if repeated intermittent restraint stress increased infarct size in a rat model of myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were subjected to no stress (control) or to daily restraint stress for 1–1.5 h for 8–14 days (stress protocol A) or for 2 h daily for 11 or 12 days (stress protocol B). Myocardial ischemia-reperfusion (30-min ischemia, 3-h reperfusion) was performed in anesthetized rats. Average baseline arterial pressures were 111 ± 4, 120 ± 10, and 125 ± 7 mmHg in the control, stress protocol A, and stress protocol B groups, respectively. Infarct size (%area at risk) was significantly larger in both groups of stressed rats compared with control rats (58 ± 5, 78 ± 2, and 79 ± 3% in the control, stress protocol A, and stress protocol B groups, respectively). During ischemia or early reperfusion, zero of eight control, two of six protocol A stress, and two of five protocol B stress rats had at least one period of severe arrhythmia. Therefore, these results provide experimental evidence corroborating correlative studies in humans that link chronic stress with increased morbidity and mortality from ischemic heart disease.

Exosomes: promising sacks for treating ischemic heart disease?

2017 ◽  
Vol 313 (3) ◽  
pp. H508-H523 ◽  
Author(s):  
Gui-Hao Chen ◽  
Jun Xu ◽  
Yue-Jin Yang
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Regeneration ◽  
Ischemic Heart ◽  
Advantages And Disadvantages ◽  
Developing Heart ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Ischemic heart disease(IHD) is the leading cause of death worldwide. Despite the development of continuously improving therapeutic strategies, morbidity and mortality of patients with IHD remain relatively high. Exosomes are a subpopulation of vesicles that are universally recognized as major mediators in intercellular communication. Numerous preclinical studies have shown that these tiny vesicles were protective in IHD, through such actions as alleviating myocardial ischemia-reperfusion injury, promoting angiogenesis, inhibiting fibrosis, and facilitating cardiac regeneration. Our review focused on these beneficial exosome-mediated processes. In addition, we discuss in detail how to fully exploit the therapeutic potentials of exosomes in the field of IHD. Topics include identifying robust sources of exosomes, loading protective agents into exosomes, developing heart-specific exosomes, optimizing isolation methods, and translating the cardioprotective effects of exosomes into clinical practice. Finally, both the advantages and disadvantages of utilizing exosomes in clinical settings are addressed.

scholarly journals Targeting Ferroptosis against Ischemia/Reperfusion Cardiac Injury

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 667
Author(s):  
José Lillo-Moya ◽  
Catalina Rojas-Solé ◽  
Diego Muñoz-Salamanca ◽  
Emiliano Panieri ◽  
Luciano Saso ◽  
...  
Keyword(s):  
Blood Flow ◽  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Ischemic Heart ◽  
Myocardial Infarct Size

Ischemic heart disease is a leading cause of death worldwide. Primarily, ischemia causes decreased oxygen supply, resulting in damage of the cardiac tissue. Naturally, reoxygenation has been recognized as the treatment of choice to recover blood flow through primary percutaneous coronary intervention. This treatment is the gold standard therapy to restore blood flow, but paradoxically it can also induce tissue injury. A number of different studies in animal models of acute myocardial infarction (AMI) suggest that ischemia-reperfusion injury (IRI) accounts for up to 50% of the final myocardial infarct size. Oxidative stress plays a critical role in the pathological process. Iron is an essential mineral required for a variety of vital biological functions but also has potentially toxic effects. A detrimental process induced by free iron is ferroptosis, a non-apoptotic type of programmed cell death. Accordingly, efforts to prevent ferroptosis in pathological settings have focused on the use of radical trapping antioxidants (RTAs), such as liproxstatin-1 (Lip-1). Hence, it is necessary to develop novel strategies to prevent cardiac IRI, thus improving the clinical outcome in patients with ischemic heart disease. The present review analyses the role of ferroptosis inhibition to prevent heart IRI, with special reference to Lip-1 as a promising drug in this clinicopathological context.

scholarly journals New Insights Into the Role of Mitochondria Quality Control in Ischemic Heart Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Yanguo Xin ◽  
Xiaodong Zhang ◽  
Jingye Li ◽  
Hui Gao ◽  
Jiayu Li ◽  
...  
Keyword(s):  
Quality Control ◽  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Mortality And Morbidity ◽  
Energy Deprivation

IHD is a significant cause of mortality and morbidity worldwide. In the acute phase, it's demonstrated as myocardial infarction and ischemia-reperfusion injury, while in the chronic stage, the ischemic heart is mainly characterised by adverse myocardial remodelling. Although interventions such as thrombolysis and percutaneous coronary intervention could reduce the death risk of these patients, the underlying cellular and molecular mechanisms need more exploration. Mitochondria are crucial to maintain the physiological function of the heart. During IHD, mitochondrial dysfunction results in the pathogenesis of ischemic heart disease. Ischemia drives mitochondrial damage not only due to energy deprivation, but also to other aspects such as mitochondrial dynamics, mitochondria-related inflammation, etc. Given the critical roles of mitochondrial quality control in the pathological process of ischemic heart disease, in this review, we will summarise the efforts in targeting mitochondria (such as mitophagy, mtROS, and mitochondria-related inflammation) on IHD. In addition, we will briefly revisit the emerging therapeutic targets in this field.

scholarly journals Botanical Flavonoids on Coronary Heart Disease

2011 ◽  
Vol 39 (04) ◽  
pp. 661-671 ◽  
Author(s):  
Chong-Zhi Wang ◽  
Sangeeta R. Mehendale ◽  
Tyler Calway ◽  
Chun-Su Yuan
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Cell Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Herbal Medicines ◽  
Grape Seed ◽  
Ischemic Heart ◽  
Care Costs

Ischemic heart disease (IHD) is one of the leading causes of death in Western countries. Prevention rather than treatment of heart disease can significantly improve patients' quality of life and reduce health care costs. Flavonoids are widely distributed in vegetables, fruits and herbal medicines. Regularly consuming botanicals, especially those containing flavonoids, has been associated with a reduction in cardiovascualar disease; thus, it is important to investigate how flavonoids improve cardiac resistance to heart disease and their related mechanisms of action. It has been shown that cardiomyocyte injury and death can result from ischemia-reperfusion, which is pathognomonic of ischemic heart disease. Massive reactive oxygen species (ROS) release at the onset of reperfusion produces cell injury and death. "Programming" the heart to either generate less ROS or to increase strategic ROS removal could reduce reperfusion response. Additionally, profuse nitric oxide (NO) release at reperfusion could be protective in "preconditioning" models. Botanical flavonoids induce preconditioning of the heart, thereby protecting against ischemia-reperfusion injury. In this article, we will discuss two herbs containing potent flavonoids, Scutellaria baicalensis and grape seed proanthocyanidin, which can potentially offer cardiac protection against ischemic heart disease.

scholarly journals The mechanism of miR-525-5p derived from hypoxia and reoxygenation in H9c2 Cardiomyocytes

2022 ◽  
Vol 67 (4) ◽  
pp. 18-23
Author(s):  
Shanshan Wang ◽  
Xin Mei ◽  
Song Ronggang ◽  
Meng Hongyan ◽  
Wei Xinfen
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Reperfusion Injury ◽  
Mrna Expression ◽  
Gene Mutation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
H9c2 Cells ◽  
H9c2 Cardiomyocytes

Ischemia-reperfusion injury (IRI) is associated with ischemic heart disease (IHD) which leads to patients a poor progression. According to Pubmed Datasets, we analyzed different gene and mRNA expressions in IHD patients with IRI. The relevant mRNA expression detected in H9C2 cells undergo hypoxia and reoxygenation, we selected and structured miR-525-5p gene mutation H9C2 cells, the results performed miR-525-5p mutated restored H9C2 metabolism of mitochondria which detected by relevant genes and proteins. At the same time, miR-525-5p silence resisted hypoxia and reoxygenation induced H9C2 cells apoptosis. All the results indicated miR-525-5p maybe protect H9C2 cells without hypoxia and reoxygenation induced injury through regulating the mitochondria metabolism.

scholarly journals From Brain to Heart: Possible Role of Amyloid-β in Ischemic Heart Disease and Ischemia-Reperfusion Injury

2020 ◽  
Vol 21 (24) ◽  
pp. 9655
Author(s):  
Giulia Gagno ◽  
Federico Ferro ◽  
Alessandra Lucia Fluca ◽  
Milijana Janjusevic ◽  
Maddalena Rossi ◽  
...  
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Reperfusion Injury ◽  
Coronary Atherosclerosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Amyloid Β ◽  
Ischemic Heart ◽  
Amyloid Angiopathy

Ischemic heart disease (IHD) is among the leading causes of death in developed countries. Its pathological origin is traced back to coronary atherosclerosis, a lipid-driven immuno-inflammatory disease of the arteries that leads to multifocal plaque development. The primary clinical manifestation of IHD is acute myocardial infarction (AMI),) whose prognosis is ameliorated with optimal timing of revascularization. Paradoxically, myocardium re-perfusion can be detrimental because of ischemia-reperfusion injury (IRI), an oxidative-driven process that damages other organs. Amyloid-β (Aβ) plays a physiological role in the central nervous system (CNS). Alterations in its synthesis, concentration and clearance have been connected to several pathologies, such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ has been suggested to play a role in the pathogenesis of IHD and cerebral IRI. The purpose of this review is to summarize what is known about the pathological role of Aβ in the CNS; starting from this evidence, we will illustrate the role played by Aβ in the development of coronary atherosclerosis and its possible implications in the pathophysiology of IHD and myocardial IRI. Better elucidation of Aβ’s contribution to the molecular pathways underlying IHD and IRI could be of great help in developing new therapeutic strategies.

scholarly journals The Mitochondrial Translocator Protein and Arrhythmogenesis in Ischemic Heart Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Lukas J. Motloch ◽  
Jun Hu ◽  
Fadi G. Akar
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Anion Channel ◽  
Permeability Transition ◽  
Ischemic Heart ◽  
Translocator Protein ◽  
Acute Ischemia ◽  
Organ Systems

Mitochondrial dysfunction is a hallmark of multiple cardiovascular disorders, including ischemic heart disease. Although mitochondria are well recognized for their role in energy production and cell death, mechanisms by which they control excitation-contraction coupling, excitability, and arrhythmias are less clear. The translocator protein (TSPO) is an outer mitochondrial membrane protein that is expressed in multiple organ systems. The abundant expression of TSPO in macrophages has been leveraged to image the immune response of the heart to inflammatory processes. More recently, the recognition of TSPO as a regulator of energy-dissipating mitochondrial pathways has extended its utility from a diagnostic marker of inflammation to a therapeutic target influencing diverse pathophysiological processes. Here, we provide an overview of the emerging role of TSPO in ischemic heart disease. We highlight the importance of TSPO in the regenerative process of reactive oxygen species (ROS) induced ROS release through its effects on the inner membrane anion channel (IMAC) and the permeability transition pore (PTP). We discuss evidence implicating TSPO in arrhythmogenesis in the settings of acute ischemia-reperfusion injury and myocardial infarction.

Abstract 300: Topical Application of IcyHot Reduces Myocardial Infarct Size in Rodents by a TRPA1-dependent Mechanism

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Yun Wu ◽  
Yao Lu ◽  
Eric R Gross
Keyword(s):  
Infarct Size ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Calcium Influx ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Sprague Dawley ◽  
Area At Risk ◽  
Reactive Aldehydes

Toxic reactive aldehydes are formed during ischemia-reperfusion. The ion channel transient receptor potential ankryin 1 (TRPA1) is irreversibly modified by reactive aldehydes which can cause calcium influx and cell death. Here we tested whether topically applied creams containing a reversible TRPA1 agonist could reduce myocardial infarct size. Male Sprague-Dawley rats 8-10 weeks age were subjected to an in vivo myocardial ischemia-reperfusion model of 30 minutes of left anterior descending (LAD) coronary artery ischemia followed by 2 hours reperfusion. Prior to ischemia, rats were untreated or had 1g of cream applied to the abdomen. The creams tested were IcyHot, Bengay, Tiger Balm, or preparation H (Fig. 1A). Hearts were negatively stained for the area at risk and the infarct size was determined by using TTC staining (Fig. 1B). A subset of rodents prior to receiving IcyHot also received an intravenous bolus of the TRPA1 antagonist TCS-5861528 (1mg/kg) or AP-18 (1mg/kg). Interestingly, both IcyHot and Bengay reduced myocardial infarct size compared to untreated rodents (Fig. 1C and 1D IcyHot: 41±3%*, Bengay: 50±2%* versus control 62±1%, n=6/group, *P<0.001). Both preparation H and Tiger Balm failed to reduce myocardial infarct size (Tiger Balm: 63±2%, preparation H 59±2%). Giving a TRPA1 antagonist prior to IcyHot also blocked the reduction in infarct size. Our additional data also indicates the methyl salicylate (mint) in IcyHot and Bengay is the agent that limits myocardial infarct size. Since IcyHot and Bengay are safely used by humans, targeting TRPA1 by using products such as these could be quickly translatable and widely used to reduce ischemia-reperfusion injury.

Abstract 16708: Cathelicidin Related Antimicrobial Peptide Treated Bone Marrow Derived Mononuclear Cells Improves Cardiac Function in a Mouse Model of Acute Myocardial Infarction: Potential Therapeutic Targets in Ischemic Heart Disease

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yuri M Klyachkin ◽  
Prabhakara R Nagareddy ◽  
Ahmed Asfour ◽  
Shaojing Ye ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Heart Disease ◽  
Cardiac Function ◽  
Ischemic Heart Disease ◽  
Infarct Size ◽  
Left Ventricular ◽  
Ischemic Heart ◽  
In Vivo Studies ◽  
Boyden Chamber ◽  
Acute Ischemic Heart Disease

Introduction: Limited stem cell retention following intracoronary administration for ischemic heart disease has reduced the clinical efficacy of this novel therapy. Cathelicidins have been shown to prime BMMNC migration towards low gradients of SDF-1 suggesting a potential role in BMMNC retention. We sought to assess the safety and efficacy of BMMNC pre-treatment with CRAMP for treatment of acute ischemic heart disease. METHODS: BMMNCs isolated from GFP mice were incubated with recombinant CRAMP (2.5 μg/ml) or placebo for 1 hour followed by chemotaxis studies towards low levels of SDF-1 (2 ng/ml) using a Boyden chamber in vitro. During the in vivo studies, mice were randomized into 3 groups: AMI followed by injection of phosphate buffered saline (PBS), BMMNCs alone, or BMMNCs incubated with CRAMP. Scar size, survival and retention of injected BMNNCs were examined by immunohistochemistry at 5 weeks. Left ventricular function was measured by echocardiography at baseline, 48 hours, and 5 weeks after MI. Changes in infarct size between 5 days and 5 weeks after AMI was assessed by cardiac MRI utilizing delayed gadolinium enhancement. RESULTS: Treatment of BMNNCs with CRAMP enhanced their migration towards low, yet physiological, levels of SDF-1 (Fig 1A). In vivo, a greater proportion of cell survival and retention was observed in the BMNNC+CRAMP group than in the BMNNC-alone group (Fig 1B) and this was associated with higher percentage of BrdU positive cells (Fig 1C). Moreover, BMNNC+CRAMP administration led to significantly better survival, improvement of cardiac function (Fig 1D-H) and reduction in infarct size compared with other control groups (Fig 1I). CONCLUSIONS: Cathelicidins enhance BMMNC retention after intramyocardial administration for acute ischemic heart disease resulting in enhanced recovery. Therapies employing this strategy may represent an effective method for improving cardiac recovery and survival rate after AMI in human studies.

Sign in / Sign up

Export Citation Format

Share Document