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      Loss of Apelin Exacerbates Myocardial Infarction Adverse Remodeling and Ischemia‐reperfusion Injury: Therapeutic Potential of Synthetic Apelin Analogues

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          Coronary artery disease leading to myocardial ischemia is the most common cause of heart failure. Apelin (APLN), the endogenous peptide ligand of the APJ receptor, has emerged as a novel regulator of the cardiovascular system.

          Methods and Results

          Here we show a critical role of APLN in myocardial infarction (MI) and ischemia‐reperfusion (IR) injury in patients and animal models. Myocardial APLN levels were reduced in patients with ischemic heart failure. Loss of APLN increased MI‐related mortality, infarct size, and inflammation with drastic reductions in prosurvival pathways resulting in greater systolic dysfunction and heart failure. APLN deficiency decreased vascular sprouting, impaired sprouting of human endothelial progenitor cells, and compromised in vivo myocardial angiogenesis. Lack of APLN enhanced susceptibility to ischemic injury and compromised functional recovery following ex vivo and in vivo IR injury. We designed and synthesized two novel APLN analogues resistant to angiotensin converting enzyme 2 cleavage and identified one analogue, which mimicked the function of APLN, to be markedly protective against ex vivo and in vivo myocardial IR injury linked to greater activation of survival pathways and promotion of angiogenesis.


          APLN is a critical regulator of the myocardial response to infarction and ischemia and pharmacologically targeting this pathway is feasible and represents a new class of potential therapeutic agents.

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          Most cited references 35

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          Angiogenesis in life, disease and medicine.

          The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and blindness. Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.
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            Left Ventricular Remodeling After Myocardial Infarction: Pathophysiology and Therapy

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              A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse.

              coronary artery ligation to induce myocardial infarction (MI) in mice is typically performed by an invasive and time-consuming approach that requires ventilation and chest opening (classic method), often resulting in extensive tissue damage and high mortality. We developed a novel and rapid surgical method to induce MI that does not require ventilation. the purpose of this study was to develop and comprehensively describe this method and directly compare it to the classic method. male C57/B6 mice were grouped into 4 groups: new method MI (MI-N) or sham (S-N) and classic method MI (MI-C) or sham (S-C). In the new method, heart was manually exposed without intubation through a small incision and MI was induced. In the classic method, MI was induced through a ventilated thoracotomy. Similar groups were used in an ischemia/reperfusion injury model. This novel MI procedure is rapid, with an average procedure time of 1.22 ± 0.05 minutes, whereas the classic method requires 23.2 ± 0.6 minutes per procedure. Surgical mortality was 3% in MI-N and 15.9% in MI-C. The rate of arrhythmia was significantly lower in MI-N. The postsurgical levels of tumor necrosis factor-α and myeloperoxidase were lower in new method, indicating less inflammation. Overall, 28-day post-MI survival rate was 68% with MI-N and 48% with MI-C. Importantly, there was no difference in infarct size or post-MI cardiac function between the methods. this new rapid method of MI in mice represents a more efficient and less damaging model of myocardial ischemic injury compared with the classic method.

                Author and article information

                J Am Heart Assoc
                J Am Heart Assoc
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                Blackwell Publishing Ltd
                August 2013
                23 August 2013
                : 2
                : 4
                [1 ]Department of Physiology, University of Alberta, Edmonton, Alberta, Canada (W.W., R.B., B.M.L., V.K., Z.K., G.Y.O.)
                [2 ]Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada (S.M.M.K., Z.W., J.C.V.)
                [3 ]Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada (W.W., V.B.P., P.Z., S.K.D., R.B., B.M.L., V.K., Z.K., G.Y.O.)
                [4 ]Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada (V.B.P., Z.W., P.Z., S.K.D., G.Y.O.)
                [5 ]Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada (G.H., A.G.M.)
                [6 ]Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (J.M.P.)
                Author notes
                Correspondence to: Gavin Y. Oudit, MD, PhD, FRCP(C), Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada. E‐mail: gavin.oudit@ 123456ualberta.ca .

                Accompanying Tables S1 through S3 and Figures S1 through S12 are available at http://jaha.ahajournals.org/content/2/4/e000249/suppl/DC1.

                © 2013 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell.

                This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Original Research
                Heart Failure


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