Journal of Clinical and Experimental Cardiology
Open Access
ISSN: 2155-9880
ISSN: 2155-9880
Short Communication - (2026)Volume 17, Issue 5
Myocardial Infarction (MI) is caused by prolonged ischemia resulting in necrosis to a portion of myocardium. Timely reperfusion to restore blood flow to ischemic myocardium is only mainstay therapy. Experimental models that mimic human Myocardial infarction include permanent closure of Left Anterior Descending coronary artery (LAD). To explore the role of EphA2 receptors and investigate the novel protective role of Doxazosin as EphA2 agonist in MI in vivo, in rats anesthetized with ketamine 80 mg/kg and xylazine 12 mg/kg i.p., intubated with endotracheal cannula using an otoscope under ventilator-assisted ventilation with extrinsic Positive End-Expiratory Pressure (PEEP), LAD ligation was performed. After LAD ligation, animals survived 4 days post-MI; biomarkers of infarction Troponin T and Troponin I and histopathological findings were performed. Doxazosin administered at low dose intravenously immediately after LAD ligation produced cardioprotective effect as manifested by reduced infarct size and Troponin T and Troponin I levels. Dot blot analysis revealed these effects were produced by activation of EphA2 receptors by Doxazosin.
Myocardial infarction; EphA2; LAD ligation; Doxazosin
Myocardial infarction is a clinical syndrome of ischemic heart disease that occur due to an irreversible damage to a portion of the myocardium due to necrosis caused by prolonged ischemia. Necrotic myocardium is surrounded by a zone of reversibly damaged myocardial cells and an ischemic zone [1]. Timely reperfusion by Percutaneous transluminal Coronary Intervention (PCI) or thrombolytic agents is essential and currently the most effective treatment to salvage ischemic myocardium [1]. Although, reperfusion using PCI has reduced mortality in developed countries, but the incidence of MI is increasing in developing countries and morbidity due to post-MI remodeling resulting in Heart failure is increasing globally [1].
Currently, the strategies aimed to regenerate damaged cardiomyocytes by stem cell therapy and enhancement of myocardial repair by promoting angiogenesis in ischemic zone require considerable improvements for clinical translation. Thus, experimental models mimicking myocardial infarction are crucial for understanding the pathological, cellular, molecular, and morphological changes occurring during and post-MI so that novel therapeutic targets or strategies for treatment can be identified and optimized for clinical translation.
In recent years, EphA receptors and their ligands, ephrinA have emerged as potential therapeutic targets to preserve myocardial function post MI. Studies by Jitka A.I. Virag and her associates has shown that intramyocardial administration of EphrinA1-Fc in peri-infarct zone has reduced inflammation, necrosis and improved cardiomyocyte survival through increased phosphorylated Akt protein [2], whereas, loss of EphA2 receptor caused worsening of myocardial injury post MI [3]. Moreover, EphrinA1-EphA2 signaling has shown to promote cardiomyocytes regeneration by stimulating migration of cardiac stem cells to infarcted myocardium [4].
Doxazosin, a selective alpha-1 adrenergic receptor (α-1) antagonist, is reported as a small molecule agonist of EphA2 and EphA4 receptors in HEK293 cell lines [5]. Similar to the native ligands (EprinA1) binding, Doxazosin (50 μM) has been shown to induce EphA2 receptor internalization and degradation [5]. Administration of Doxazosin (0.06 mg/kg for 14 days) is shown to enhance angiogenesis in ischemic hindlimb without altering systemic blood pressure [6].
In our lab, the role of EphA2 receptors in mediating cardioprotective effect of Doxazosin against myocardial ischemia-reperfusion injury has been explored in isolated rat heart [7]. It was observed that ischemic postconditioning as well as pharmacological postconditioning employing Doxazosin (25 μM and 50 μM) as specific EphA2 agonist prevented ischemia and reperfusion induced myocardial injury probably through activation of EphA2 receptors, as postconditioning induced cardioprotection was abrogated by EphA2 receptor antagonist, Lithocholic acid. The protective effect of postconditioning was abolished by Wortmannin, a PI3K inhibitor, thus, PI3/Akt pathway may have a prominent role in EphA2 receptor mediated cardioprotection [7].
Currently, in a pilot study, we have investigated the effect of Doxazosin as EphA2 receptor agonist in myocardial infarction in vivo induced by permanent closure of LAD in rats. The rats were anesthetized with ketamine 80 mg/kg and xylazine 12 mg/kg i.p. and intubated with an endotracheal cannula using an otoscope under ventilator-assisted ventilation. Then, left-sided thoracotomy with minimal invasive lesion was performed to expose heart followed by ligation of LAD and animals were survived for four days post MI [8]. Administration of low dose Doxazosin intravenously immediately after LAD ligation in rats produced a cardioprotective effect as manifested by decrease in infarct size, serum troponin T and troponin I levels. For detection of EphA2 receptors activation by Doxazosin, dot blot analysis was performed. The results of dot blot analysis revealed the presence of EphA2 protein in sham hearts, whereas in LAD ligated rats, intensity signal for EphA2 decreased. In Doxazosin 60 μg/kg i.v. treated hearts intensity signal for EphA2 protein is increased.
Doxazosin, as selective α1-adrenergic receptor antagonist, act as an effective antihypertensive agent that exhibits beneficial effects on atherogenic risk factors such as increase in levels of cardioprotective lipids; inhibit platelet aggregation and increase fibrinolysis. Doxazosin is used as an add-on therapy in hypertension but not used as first line drug due to adverse effects edema and hypotension caused by α-1 receptor blockade.
The protective effect produced by low-dose Doxazosin intravenously in LAD ligated rats mediated through EphA2 receptor activation may serve as beneficial approach against MI and avoid vasodilator adverse effects due to α-1 antagonism by Doxazosin.
Limitation of this study was that due to poor aqueous solubility of Doxazosin, it was dissolved in 1% DMSO as co-solvent and 99% saline to perform a pilot study in LAD ligated rats.
Thus, the novel role of EphA2 activation by low-dose Doxazosin can serve as potential therapeutic strategy that can be beneficial for Myocardial Infarction studies must be designed to develop an intravenous formulation of low-dose Doxazosin and investigate its cardioprotective effect employing in vivo model of Myocardial infarction mediated through cardiac EphA2 receptors.
Dr. Ravi Kumar Dhawan, Principal, Khalsa College of Pharmacy, Amritsar, for providing guidance and support to purchase all surgical equipment; Management of Khalsa College Governing Council for providing funds; Dr. Nirmal Singh, Ex-HOD, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala for finalizing the research idea of Postconditioning; Dr. Harish Kumar Verma, Principal, Khalsa College of Veterinary and Animal Sciences, Amritsar for providing gift sample of Ketamine and Xylazine; Dr. Rekha Singh, Histopathology Department, Fortis Memorial Research Institute, Gurugram for Histopathology facilities and grading; Mr. Hemaant Arora, M.D., Universal Diagnostics providing facility for Troponin I evaluation; Dr Rachna Hora, Associate Prof, Department of Molecular Biology and Biochemistry for blotting techniques; Mr. Mangal Singh Zandu, Additional Standing Counsel of Govt of India, for providing financial support in publication charges.
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Citation: Kaur K, Kashyap K, Sharma N, Gulati P, Dhawan RK, Singh N (2025). EphA2 Receptor Activation by Doxazosin as Potential Therapeutic Strategy Beneficial for Myocardial Infarction and Ischemia-Reperfusion Injury. J Clin Exp Cardiolog. 16:985.
Received: 15-Nov-2025, Manuscript No. JCEC-25-39178; Editor assigned: 17-Nov-2025, Pre QC No. JCEC-25-39178 (PQ); Reviewed: 06-Jan-2026, QC No. JCEC-25-39178; Revised: 13-Jan-2026, Manuscript No. JCEC-25-39178 (R); Published: 20-May-2026 , DOI: 10.35248/2155-9880.26.17.1006
Copyright: © 2025 Kaur K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.