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Genetic Modification of Cardiac Tissue

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Front. Cardiovasc. Med. | doi: 10.3389/fcvm.2019.00031

Telomerase deficiency predisposes to heart failure and ischemia-reperfusion Injury

 Karima Ait-Aissa1*, James S. Heisner2, Laura Norwood Toro1, Bruemmer Dennis3, Genevieve Doyon3, Leanne Harmann1,  Aron Geurts1,  Amadou K. Camara2 and  Andreas M. Beyer1
  • 1Department of Medicine, Medical College of Wisconsin, United States
  • 2Department of Anesthesiology, Medical College of Wisconsin, United States
  • 3University of Pittsburgh, United States

Introduction: Elevated levels of mitochondrial reactive oxygen species (ROS) contribute to the development of numerous cardiovascular diseases. TERT, the catalytic subunit of telomerase, has been shown to translocate to mitochondria to suppress ROS while promoting ATP production. Acute overexpression of TERT increases survival and decreases infarct size in a mouse model of myocardial infarct, while decreased telomerase activity predisposes to mitochondrial defects and heart failure. In the present study, we examined the role of TERT on cardiac structure and function under basal conditions and conditions of acute or prolonged stress in a novel rat model of TERT deficiency. Methods: Cardiac structure and function were evaluated via transthoracic echocardiogram. Langendorff preparations were used to test the effects of acute global ischemia reperfusion injury on cardiac function and infarction. Coronary flow and left ventricular pressure were measured during and after ischemia/reperfusion (/R). Mitochondrial DNA integrity was measured by PCR and mitochondrial respiration was assessed in isolated mitochondria using an Oxygraph. Angiotensin II infusion was used as an established model of systemic stress. Results: No structural changes (echocardiogram) or coronary flow/ left ventricle pressure (isolated hearts) were observed in TERT-/- rats at baseline; however, after I/R, coronary flow was significantly reduced in TERT-/- compared to wild type (WT) rats, while diastolic Left Ventricle Pressure was significantly elevated (n=6 in each group; p<0.05) in the TERT-/-. Interestingly, infarct size was less in TERT-/- rats compared to WT rats, while mitochondrial respiratory control index decreased and mitochondrial DNA lesions increased in TERT-/- compared to WT controls. Angiotensin II treatment did not alter cardiac structure or function; however, it augmented the infarct size significantly more in TERT-/- compared to the Wildtype. Conclusion: Absence of TERT activity increases susceptibility to stress following cardiac injury. These results suggest a critical role of telomerase in chronic heart disease.

Keywords: Telomerase (TERT), ischema-reperfusion injury, Mitochondia, Heart disease, reactive oxygen species

Received: 06 Aug 2018; Accepted: 07 Mar 2019.

Edited by:

Edward J. Lesnefsky, Virginia Commonwealth University, United States

Reviewed by:

Sabzali Javadov, School of Medicine, University of Puerto Rico, Puerto Rico
Jin O-Uchi, University of Minnesota Twin Cities, United States
Fouad Zouein, American University of Beirut, Lebanon  

Copyright: © 2019 Ait-Aissa, Heisner, Norwood Toro, Dennis, Doyon, Harmann, Geurts, Camara and Beyer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Karima Ait-Aissa, Medical College of Wisconsin, Department of Medicine, Milwaukee, United States,