Michael G. Katz, MD, PhD, Elizabeth Brandon-Warner, PhD, Anthony S

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Mitigation of myocardial fibrosis by molecular cardiac surgery–mediated gene overexpression Michael G. Katz, MD, PhD, Elizabeth Brandon-Warner, PhD, Anthony S. Fargnoli, PhD, Richard D. Williams, BS, Andrew P. Kendle, BS, Roger J. Hajjar, MD, Laura W. Schrum, PhD, Charles R. Bridges, MD, ScD The Journal of Thoracic and Cardiovascular Surgery Volume 151, Issue 4, Pages 1191-1200.e3 (April 2016) DOI: 10.1016/j.jtcvs.2015.11.031 Copyright © 2016 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Western blot quantifying SERCA2a protein expression in the BZ of small MI, large MI, and large MI with SERCA groups. SERCA2a, Sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a; MI, myocardial infarction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. *P < .01, versus small MI, large MI. The Journal of Thoracic and Cardiovascular Surgery 2016 151, 1191-1200.e3DOI: (10.1016/j.jtcvs.2015.11.031) Copyright © 2016 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 A-C, Messenger ribonucleic acid expression levels of TGFβ1 signaling components and downstream target [Colα1(I)] were assessed in heart tissue from: (A) IZ; (B) BZ; and (C) RZ. D, Protein content in IZ and BZ of Colα1(I), TGFβ1, TGFβRII, and Smad3, as measured by Western blot for control, large MI with SERCA, small MI, and large MI groups. GAPDH protein expression measured for normalization. TGFβ, Transforming growth factor beta; Smad, an intracellular signaling protein family; Colα1, Collagen alpha 1 type 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MI, myocardial infarction; SERCA, sarcoplasmic reticulum calcium adenosine triphosphatase; IZ, infarct zone; BZ, border zone. *P < .05 versus small MI, large MI with SERCA2a. The Journal of Thoracic and Cardiovascular Surgery 2016 151, 1191-1200.e3DOI: (10.1016/j.jtcvs.2015.11.031) Copyright © 2016 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Changes in (A) αSMA protein as well as (B) fibronectin protein, measured using Western blot, normalized to GAPDH. αSMA, alpha smooth muscle actin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MI, myocardial infarction; SERCA, sarcoplasmic reticulum calcium adenosine. *P < .05 versus large MI with SERCA. †P < .05 versus control. The Journal of Thoracic and Cardiovascular Surgery 2016 151, 1191-1200.e3DOI: (10.1016/j.jtcvs.2015.11.031) Copyright © 2016 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Herovici staining was performed in IZ, BZ, and RZ in each group. A-C, IZ; (D-F) BZ; (G-I) RZ. Arrows mark collagen fibrils. x20 magnification. Blue staining indicates new collagen fibrils; red staining indicates mature collagen fibrils. (J) Quantification of de novo (new) to mature collagen deposition assessed by Herovici staining. MI, Myocardial infarction; SERCA, sarcoplasmic reticulum calcium adenosine; IZ, infarct zone; BZ, border zone; RZ, remote zone. *P < .05 versus small MI. †P < .05 versus large MI with SERCA. The Journal of Thoracic and Cardiovascular Surgery 2016 151, 1191-1200.e3DOI: (10.1016/j.jtcvs.2015.11.031) Copyright © 2016 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 A-F, Transmission electron microscopy images of BZ and RZ tissue from each group. Examples of m and mf with clearly delineated sarcomeres are labeled. Varying degrees of mitochondrial fragmentation and cristae destruction are shown (black arrows) along with twin T tubules (white arrows). Images ×10,500 magnified, scale bar: 2 μm. G, Semiquantitative analysis of myofibrillar disruption seen in images A-F. MI, Myocardial infarction; BZ, border zone; m, mitochondria; mf, myofibrils; RZ, remote zone; SERCA, sarcoplasmic reticulum calcium adenosine. The Journal of Thoracic and Cardiovascular Surgery 2016 151, 1191-1200.e3DOI: (10.1016/j.jtcvs.2015.11.031) Copyright © 2016 The American Association for Thoracic Surgery Terms and Conditions

Figure 6 Proposed mechanism of action from initial Ca2+ imbalance due to SERCA2a down-regulation through Ang II and TGF-β signaling to fibrosis. TGFβ, Transforming growth factor beta; Ang II, angiotensin II; Smad, SMAD family signal transduction proteins; NADPH, nicotinamide adenine dinucleotide phosphate; NFATc, nuclear factor of activated T-cells, cytoplasmic; GATA4, GATA family zinc finger transcription factor 4; DNA, deoxyribonucleic acid; AP1, transcription factor; P38 MAPK, p38 mitogen-activated protein kinases; PKC, protein kinase C; SERCA2a, sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a; MI, myocardial infarct. The Journal of Thoracic and Cardiovascular Surgery 2016 151, 1191-1200.e3DOI: (10.1016/j.jtcvs.2015.11.031) Copyright © 2016 The American Association for Thoracic Surgery Terms and Conditions

Figure E1 A-D, Immunohistochemical DAB staining (brown) for AT1R in myocardium of (A) control; (B) large MI/SERCA; (C) small MI; and (D) large MI groups. E, Angiotensin II plasma levels; (F) AT1R expression. Whisker-plot analysis shows total range of AT1R positive cells (determined by DAB immunohistochemistry) across all heart sections. The solid line in the middle represents the median; upper and lower crossbars encompass the middle 50th percentile. MI, Myocardial infarction; SERCA, sarcoplasmic reticulum calcium adenosine triphosphatase; AT1R, angiotensin II receptor 1. The Journal of Thoracic and Cardiovascular Surgery 2016 151, 1191-1200.e3DOI: (10.1016/j.jtcvs.2015.11.031) Copyright © 2016 The American Association for Thoracic Surgery Terms and Conditions

Proposed mechanism due to SERCA2a down-regulation through angiotensin II and TGF-β to fibrosis. The Journal of Thoracic and Cardiovascular Surgery 2016 151, 1191-1200.e3DOI: (10.1016/j.jtcvs.2015.11.031) Copyright © 2016 The American Association for Thoracic Surgery Terms and Conditions