Left Ventricular Unloading After Acute Myocardial Infarction Reduces MMP/JNK Associated Apoptosis and Promotes FAK Cell-Survival Signaling Tieluo Li,

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Left Ventricular Unloading After Acute Myocardial Infarction Reduces MMP/JNK Associated Apoptosis and Promotes FAK Cell-Survival Signaling Tieluo Li, MD, Xufeng Wei, MD, PhD, Charles F. Evans, MD, Pablo G. Sanchez, MD, PhD, Shuying Li, MD, Zhongjun J. Wu, PhD, Bartley P. Griffith, MD The Annals of Thoracic Surgery Volume 102, Issue 6, Pages 1919-1924 (December 2016) DOI: 10.1016/j.athoracsur.2016.05.007 Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 Schematic diagram showing the β1D-integrin/focal adhesion kinase (FAK)/c-Jun N-terminal kinase (JNK) pathway of antiapoptosis and the matrix metalloproteinase (MMP)-2 pathway of myocardial apoptosis. Mechanical stretch (strain) activates integrin-linked focal adhesion complex and phosphorylates FAK at various tyrosine residues. Phosphorylated FAK (p-FAK) blocks the phosphorylation of JNK, leading to the inhibition of myocyte apoptosis. In addition, decompensated cardiomyopathy mediates production of MMP-2s. MMP-2s inhibit β1D-integrin mediated FAK phosphorylation leading to reversal of β1D-integrin induced antiapoptotic pathway and promote apoptotic signaling pathways. The Annals of Thoracic Surgery 2016 102, 1919-1924DOI: (10.1016/j.athoracsur.2016.05.007) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 Antiapoptotic effect of left ventricular (LV) unloading. (A) Typical blotting in matrix metalloproteinase (MMP)-2/c-Jun N-terminal kinase (JNK) apoptotic pathway, (B) pro-MMP-2, (C) MMP-2, (D) JNK, (E) phosphorylated (p)-JNK. (GAPDH = glyceraldehyde-3-phosphate dehydrogenase; LVAD = left ventricular assist device; MI = myocardial infarction.) The Annals of Thoracic Surgery 2016 102, 1919-1924DOI: (10.1016/j.athoracsur.2016.05.007) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 (A, B) TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling) staining. *p < 0.05 compared with all groups and zone. (LA = adjacent zone at myocardial infarction+left ventricular assist device group; LR = remote zone at myocardial infarction+left ventricular assist device group; MA = adjacent zone at myocardial infarction group; MR = remote zone at myocardial infarction group; PC = positive control; SA = sham adjacent zone.) The Annals of Thoracic Surgery 2016 102, 1919-1924DOI: (10.1016/j.athoracsur.2016.05.007) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 Integrin/focal adhesion kinase (FAK) survival pathway effects of left ventricular (LV) unloading. (A) Typical blotting in integrin/FAK survival pathway. *Unspecific band. (B) Intact β1d integrin. *p < 0.05 compared with all groups and zone. (C) β1d integrin fragment. *p < 0.05 compared with myocardial infarction (MI) group and MI+left ventricular assist device (LVAD) group. †p < 0.05 compared with remote zone. (D) Focal adhesion kinase (FAK, (E) phosphorylated (p)-FAK. *p < 0.05 compared with remote zone of MI group and MI+LVAD group. †p < 0.05 compared with remote zone; ‡p < 0.05 compared with adjacent zone of MI group. (GAPDH = glyceraldehyde-3-phosphate dehydrogenase.) The Annals of Thoracic Surgery 2016 102, 1919-1924DOI: (10.1016/j.athoracsur.2016.05.007) Copyright © 2016 The Society of Thoracic Surgeons Terms and Conditions