Journal
INTERNATIONAL JOURNAL OF CARDIOLOGY
Volume 341, Issue -, Pages 24-30Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.ijcard.2021.07.021
Keywords
PDGF-A; Gene therapy; Myocardial infarction; Angiogenesis; Scar
Categories
Funding
- National Health and Medical Research Council [APP1100046]
- National Heart Foundation, Australia [100463]
- Stem Cells Australia Project Grant
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Overexpression of Pdgf-a in the post-MI heart can modulate scar composition and improve left ventricular function, highlighting the potential of rAAV gene transfer of Pdgf-a as a cardio-reparative therapy.
Background: Novel therapies that can limit or reverse damage caused by myocardial infarction (MI) could ease the increasing burden of heart failure. In this regard Platelet Derived Growth Factor (PDGF) has been previously shown to contribute to cardiac repair after MI. Here, we use a rodent model of MI and recombinant adenoassociated virus 9 (rAAV9)-mediated gene transfer to overexpress Pdgf-a in the injured heart and assess its therapeutic potential. Methods and results: Sprague Dawley rats underwent temporary occlusion of the left anterior descending coronary artery, followed immediately by systemic delivery of 1 x 10<^>11 vector genomes of either rAAV9 Pdgf-a or rAAV9 Empty vector (control). At day 28 post-MI echocardiography showed significantly improved left ventricular (LV) function (fractional shortening) after rAAV9 Pdgf-a (0.394 +/- 0.019%) treatment vs control (0.304 +/- 0.018%). Immunohistochemical analysis demonstrated significantly increased capillary and arteriolar density in the infarct border zone of rAAV9 Pdgf-a treated hearts together with a significant reduction in infarct scar size (rAAV9 Pdgf-a 6.09 +/- 0.94% vs Empty 12.45 +/- 0.92%). Western blot and qPCR analyses confirmed overexpression of PDGF-A and showed upregulation of smooth muscle alpha actin (Acta2), collagen type III alpha 1 (Col3a1) and lysyl oxidase (Lox) genes in rAAV9 Pdgf-a treated infarcts. Conclusion: Overexpression of Pdgf-a in the post-MI heart can modulate scar composition and improve LV function. Our study highlights the potential of rAAV gene transfer of Pdgf-a as a cardio-reparative therapy.
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