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Therapeutic Potential of EPO and its Derivatives for Reducing Blood Pressure

EPO 及其衍生物降低血压的治疗潜力

基本信息

批准号：
9147229
负责人：
Edward Lakatta
金额：
$ 15.43万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9147229
关键词：
Abdominal Cavity Acute Adverse effects Anemia Animal Experiments Animals Anti-Inflammatory Agents Anti-inflammatory Antihypertensive Agents Aorta Apoptotic Area Arteries Attenuated Binding Blast Cell Blood Cells Blood Pressure Blood Pressure Monitors Blood Vessels Breathing Cardiac Cardiac Myocytes Cardiovascular system Catheters Control Groups Coronary Coronary artery Dahl Hypertensive Rats Data Development Diet Dose Equilibrium Erythrocytes Erythropoietin Erythropoietin Receptor Excision Experimental Models Glycoproteins Heart failure Hormones Hour Human Hypertension Implant Inbred SHR Rats Indwelling Catheter Infusion procedures Inhibition of Apoptosis Injection of therapeutic agent Intravenous Isoflurane Kidney Diseases Left ventricular structure Life Expectancy Ligation Maintenance Measures Mediating Medical Mitochondria Modeling Molecular Structure Myocardial Infarction Myocardial Ischemia NG-Nitroarginine Methyl Ester Nephrosclerosis Nerve Tissue Nitric Oxide Nitric Oxide Pathway Nitric Oxide Signaling Pathway Nitric Oxide Synthetase Inhibitor Pathway interactions Peptides Performance Peripheral Permeability Pharmaceutical Preparations Pharmacologic Substance Process Production Property Publishing Pump Rattus Reactive Oxygen Species Recombinant Erythropoietin Recombinants Regulation Renal Mass Reporting Research Risk Factors Role Saline Sodium Chloride Sodium-Restricted Diet Stress Stroke Surface Tail Techniques Telemetry Testing Therapeutic Time Tissues Translations Vasodilation Wistar Rats Writing base blood pressure reduction blood pressure regulation clinical practice coronary fibrosis hemodynamics intravenous injection myocardial infarct sizing normotensive novel therapeutic intervention pre-clinical pressure prevent programs receptor recombinant human erythropoietin research study response sensor

项目摘要

The broad objective of this program is to explore the vasodilative potential of rhEPO and its non-erythropoietic derivatives and to perform preclinical animal experiments on different models of arterial hypertension to elucidate their mechanism of action and to evaluate their potential for translation into clinical practice in humans. I. Acute hemodynamic effects of EPO. Recently published research strongly suggests the erythropoietin binds to a Common receptor and therefore activates anti-apoptotic, anti-inflammatory pathways, and nitric oxide release. Surprisingly, hemodynamic response subsequent to NO activation after EPO administration had never been reported. Objectives of this study were to evaluate the acute hemodynamic and cardiovascular responses to EPO administration, to confirm their NO association, and to test the hypothesis that EPO-induced cardioprotection is mediated through cardiovascular changes related to NO activation. In Experiment 1 after 3000 U/kg of rhEPO was administered intravenously to Wistar rats, arterial blood pressure, monitored via indwelling catheter, almost immediately started progressively to decline, until leveling off 90 minutes after injection at 20% below control level. In Experiment 2 the 25% reduction of mean blood pressure, compared to control group, was observed 2 hrs after intravenous injection of either 3000 or 150 U/kg of rhEPO. Detailed pressure volume loop analyses of cardiac performance (Experiment 3) 2 hrs after intravenous injection of human or rat recombinant EPO (3000U/kg) revealed a significant reduction of systolic function (PRSW was 33% less than control). Reduction of arterial blood pressure and systolic cardiac function in response to rhEPO were blocked in rats pretreated with a non-selective inhibitor of nitric oxide synthase (L-NAME). In Experiment 4, 24 hrs after a permanent ligation of a coronary artery myocardial infarction (MI) measured 263.5% of left ventricle in untreated rats. MI in rats treated with 3000 U/kg of rhEPO immediately after coronary ligation was 56% smaller. Pretreatment with L-NAME did not attenuate the beneficial effect of rhEPO on MI size, while MI size in rats treated with L-NAME alone did not differ from control. Therefore, a single injection of rhEPO resulted in a significant, NO-mediated reduction of systemic blood pressure and corresponding reduction of cardiac systolic function. However, EPO-induced protection of myocardium from ischemic damage is not associated with NO activation or NO-mediated hemodynamic responses. II. Antihypertensive properties of non-erythropoietic derivatives of EPO A small peptide, Helix B Surface Peptide (HBSP), also known as ARA290, was synthesized by Araim Pharmaceutical on the basis of a part of the EPO molecule. This peptide binds to a common receptor, EPO receptor hetherocomplex, and does not have pro-thrombotic effects. This peptide was tested in different experimental models and, while it proved to possess strong tissue protective properties, it did not induce blood cell production. Recently we demonstrated that HBSP has a similar potency to rhEPO for increasing the reactive oxygen species (ROS) threshold for induction of the mitochondrial permeability transition by 40%, thus protecting cardiac myocytes from ischemic stress. In the rat model of MI induced by a permanent ligation of the coronary artery, we also demonstrated the equal potency of a single administration of EPO and HBSP for a 50% reduction of resulting MI. In that experimental model the anti-apoptotic and anti-inflammatory potentials of HBSP were equal to those of rhEPO. In the first experiment, under Isoflurane inhalation narcosis, after recording of arterial blood pressure via catheter inserted into the aorta, we administered either a single intravenous dose of 60 mcg of HBSP (ARA290) or a saline to a normotensive rat. Two hours later the Isoflurane was reintroduced and arterial blood pressure was again measured. The blood pressure after injection of peptide was about 20% lower than after injection of saline. The effect was similar to the effect of rhEPO that we previously reported and was blocked by pretreatment with L-NAME. In the second experiment the arterial blood pressure reducing effect of HBSP was tested in 3 different experimental rat models of hypertension. Osmotic pumps delivering 0.16 - 0.09 ug/min of HBSP for 8 weeks were implanted into the abdominal cavity of spontaneously hypertensive rats (SHR), salt sensitive Dahl rats consuming a high salt diet (HS), and Wistar rats subjected to a resection of 5/6 of the total renal mass (RMR). WKY, Dahl salt sensitive rats maintained on a low salt diet, and sham operated rats, respectively, served as controls for these 3 models. Blood pressure was measured under Isoflurane narcosis using tail cuff technique. In untreated groups of all three experimental models, systolic blood pressure (SBP) gradually increased to 180-200 mmHg. HBSP infusion completely normalized the SBP in SHR, reduced the SBP by 20% (from 190 to 150 mmHg) in RMR, and prevented the elevation of SBP in Dahl salt sensitive rats maintained on high salt diet. Significant myocardial fibrosis occurring in all 3 groups of untreated hypertensive rats was reduced to the level of controls by HBSP. Significant nephrosclerosis observed in all 3 untreated hypertensive groups was also reduced to the level of controls in treated Dahl and SHR, but not in RMR groups. These results clearly demonstrate potent antihypertensive and antifibrotic properties of HBSP. In order to investigate antihypertension effect of HBSP for long-term in un-anesthetized, freely-moving animals, during this reporting period, we used implantable blood pressure telemetry sensors in spontaneously hypertensive rats (SHR), treat one half of them with HBSP (0.16 - 0.09 ug/min via mini-osmotic pump) and other half with saline (via mini-osmotic pump) for 8 weeks. At the time this report is written, data are still in the process.

该项目的主要目的是探索rhEPO及其非红细胞衍生物的血管扩张潜能，并在不同的动脉高血压模型上进行临床前动物实验，以阐明其作用机制，并评估其在人类临床实践中的应用潜力。