Mitigation of myocardial fibrosis by molecular cardiac surgery–mediated gene overexpression

• Published in: The Journal of thoracic and cardiovascular surgery Vol. 151; no. 4; pp. 1191 - 1200.e3
• Main Authors: Katz, Michael G., MD, PhD, Brandon-Warner, Elizabeth, PhD, Fargnoli, Anthony S., PhD, Williams, Richard D., BS, Kendle, Andrew P., BS, Hajjar, Roger J., MD, Schrum, Laura W., PhD, Bridges, Charles R., MD, ScD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2016
• Subjects: Angiotensin II - metabolism; Animals; Calcium - metabolism; Cardiomyopathies - enzymology; Cardiomyopathies - genetics; Cardiomyopathies - pathology; Cardiomyopathies - physiopathology; Cardiomyopathies - therapy; Cardiothoracic Surgery; Collagen - metabolism; Disease Models, Animal; Enzyme Induction; Fibronectins - metabolism; Fibrosis; gene therapy; Genetic Therapy - methods; Heart Failure - enzymology; Heart Failure - genetics; Heart Failure - pathology; Heart Failure - physiopathology; Heart Failure - prevention & control; Hemodynamics; Male; myocardial infarction; Myocardial Infarction - enzymology; Myocardial Infarction - genetics; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocardium - enzymology; Myocardium - pathology; Myofibroblasts - enzymology; Myofibroblasts - pathology; Receptor, Angiotensin, Type 1 - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases - biosynthesis; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sheep; TGFbeta; Time Factors; Transforming Growth Factor beta - metabolism; MCARD; transforming growth factor beta; myocardial infarction; RZ; 3,3′-diaminobenzidine; sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a; SERCA2a; border zone; Ca 2; BZ; SMAD; MI; TGFbeta; angiotensin II receptor 1; molecular cardiac surgery with recirculating delivery; DAB; AAV1; infarct zone; gene therapy; calcium ion; IZ; adeno-associated viral vector, serotype 1; AT 1R; an intracellular signaling protein family; TGFβ; remote zone; fibrosis; AT1R; Ca2
• ISSN: 0022-5223; 1097-685X
• DOI: 10.1016/j.jtcvs.2015.11.031

Abstract Objective Heart failure is accompanied by up-regulation of transforming growth factor beta signaling, accumulation of collagen and dysregulation of sarcoplasmic reticulum calcium adenosine triphosphatase cardiac isoform 2a (SERCA2a). We examined the fibrotic response in small and large myocardial infarct, and the effect of overexpression of the SERCA2a gene. Methods Ischemic cardiomyopathy was induced via creation of large or small infarct in 26 sheep. Animals were divided into 4 groups: small infarct; large infarct with heart failure; gene-treated (large infarct with heart failure followed by adeno-associated viral vector, serotype 1.SERCA2a gene construct transfer by molecular cardiac surgery with recirculating delivery); and control. Results Heart failure was significantly less pronounced in the gene-treated and small-infarct groups than in the large-infarct group. Expression of transforming growth factor beta signaling components was significantly higher in the large-infarct group, compared with the small-infarct and gene-treated groups. Both the angiotensin II type 1 receptor and angiotensin II were significantly elevated in the small- and large-infarct groups, whereas gene treatment diminished this effect. Active fibrosis with de novo collagen synthesis was evident in the large-infarct group; the small-infarct and gene-treated groups showed less fibrosis, with a lower ratio of de novo to mature collagen. Conclusions The data presented provide evidence that progression of fibrosis is mediated through increased transforming growth factor beta and angiotensin II signaling, which is mitigated by increased SERCA2a gene expression.