Original ArticleAntiapoptotic Effect of β1 Blockers in Ascending Thoracic Aortic Smooth Muscle Cells The Role of HSP70 ExpressionRizos, Ioannis K. MD*; Tsoporis, James N. PhD†; Toumpoulis, Ioannis K. MD, PhD‡; Salpeas, Vasileios MD, PhD*; Izhar, Shehla BSc†; Rigopoulos, Angelos G. MD, PhD*; Sakadakis, Eleftherios A. MD, PhD*; Parker, Thomas G. MD†Author Information *2nd Academic Department of Cardiology, Attikon University Hospital, University of Athens Medical School, Athens, Greece; †Division of Cardiology, Department of Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; and ‡Department of Cardiothoracic Surgery, Attikon University Hospital, University of Athens Medical School, Athens, Greece. Reprints: James N. Tsoporis, PhD, Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada (e-mail: firstname.lastname@example.org). Supported by grants to T. G. Parker from the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research. The authors report no conflicts of interest. Received July 03, 2017 Accepted April 12, 2018 Journal of Cardiovascular Pharmacology: August 2018 - Volume 72 - Issue 2 - p 86-96 doi: 10.1097/FJC.0000000000000596 Buy Metrics Abstract Abstract: Heat shock proteins (HSPs) play an important role in the cellular adaptation to stress, a requisite for cell survival. The aortic wall appears to be a target for increased expression of HSPs during surgical stress. We aimed to define the expression and function of aortic HSP70 in 31 patients with normal ascending thoracic aortic diameter who underwent aortic valve replacement due to aortic valve stenosis and in 35 patients with dilated ascending thoracic aorta who underwent replacement of an ascending thoracic aortic aneurysm. To elucidate responsible signaling mechanisms we used an in vitro model of rat hypoxic aortic vascular smooth muscle cell (AVSMC) cultures. We demonstrated an increase in AVSMC HSP70 and an attenuation of the apoptotic markers (TUNEL-positive nuclei, caspase-3 activity, Bax/Bcl2 ratio) in aortic wall tissue specimens from both aortic valve stenosis and ascending thoracic aortic aneurysm patients on β1 blockade with metoprolol. In vitro, metoprolol treatment of hypoxic rat AVSMCs increased nitric oxide (NO) production, induced heat shock factor 1 transport to the nucleus, upregulated HSP70, decreased p53 phosphorylation and attenuated apoptosis. Blockade of NO production, resulted in decreased HSP70 and prevented the metoprolol-induced anti-apoptotic response of hypoxic AVSMCs. We demonstrate an anti-apoptotic effect of metoprolol dependent on NO-induced HSP70 expression, and thus augmentation of HSP70 expression should be considered as a therapeutic approach to limit apoptosis in the human ascending thoracic aorta of patients undergoing cardiac surgery. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.