Shuyuan Chen1, Jiaxi Chen2, Pintong Huang3, Xing-Li Meng1, Sandra Clayton1, Jin-Song Shen1, Paul A Grayburn4. 1. Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX, USA. 2. The University of Texas Southwestern Medical Center at Dallas, Medical School, 5235 Harry Hine Blvd., Dallas, TX, USA. 3. Department of Ultrasonography, The 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, China. 4. Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX, USA; Department of Internal Medicine, Division of Cardiology, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N. Hall St, Suite H030, Dallas, TX, USA. Electronic address: paulgr@baylorhealth.edu.
Abstract
UNLABELLED: Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. METHODS AND RESULTS: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. CONCLUSIONS: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration.
UNLABELLED: Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. METHODS AND RESULTS: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycincardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycincardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. CONCLUSIONS: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycincardiomyopathy by stimulating myocardial regeneration.
Authors: Klazina Kooiman; Silke Roovers; Simone A G Langeveld; Robert T Kleven; Heleen Dewitte; Meaghan A O'Reilly; Jean-Michel Escoffre; Ayache Bouakaz; Martin D Verweij; Kullervo Hynynen; Ine Lentacker; Eleanor Stride; Christy K Holland Journal: Ultrasound Med Biol Date: 2020-03-10 Impact factor: 2.998