title: Low-Intensity Pulsed Ultrasound Enhances Angiogenesis and Ameliorates Left Ventricular Dysfunction in a Mouse Model of Acute Myocardial Infarction.
abstract: Left ventricular (LV) remodeling after acute myocardial infarction still remains an important issue in cardiovascular medicine. We have recently demonstrated that low-intensity pulsed ultrasound (LIPUS) therapy improves myocardial ischemia in a pig model of chronic myocardial ischemia through enhanced myocardial angiogenesis. In the present study, we aimed to demonstrate whether LIPUS also ameliorates LV remodeling after acute myocardial infarction and if so, to elucidate the underlying molecular mechanisms involved in the beneficial effects of LIPUS.
  
  
  
  We examined the effects of LIPUS on LV remodeling in a mouse model of acute myocardial infarction, where the heart was treated with either LIPUS or no-LIPUS 3 times in the first week (days 1, 3, and 5). The LIPUS improved mortality and ameliorated post-myocardial infarction LV remodeling in mice. The LIPUS upregulated the expression of vascular endothelial growth factor, endothelial nitric oxide synthase, phosphorylated ERK, and phosphorylated Akt in the infarcted area early after acute myocardial infarction, leading to enhanced angiogenesis. Microarray analysis in cultured human endothelial cells showed that a total of 1050 genes, including those of the vascular endothelial growth factor signaling and focal adhesion pathways, were significantly altered by the LIPUS. Knockdown with small interfering RNA of either β1-integrin or caveolin-1, both of which are known to play key roles in mechanotransduction, suppressed the LIPUS-induced upregulation of vascular endothelial growth factor. Finally, in caveolin-1-deficient mice, the beneficial effects of LIPUS on mortality and post-myocardial infarction LV remodeling were absent.
  
  
  
  These results indicate that the LIPUS therapy ameliorates post-myocardial infarction LV remodeling in mice in vivo, for which mechanotransduction and its downstream pathways may be involved.
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Shindo
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan. ito-kenta@cardio.med.tohoku.ac.jp.
authors.forename: Kenta
authors.initials: K
authors.lastname: Ito
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ogata
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Hatanaka
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kurosawa
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Eguchi
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kagaya
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hanawa
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Aizawa
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiroto
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Kasukabe
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyata
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Taki
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanai
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medicine (T. Shindo, K.T., T.O., K. Hatanaka, R.K., K.E., Y.K., K. Hanawa, K.A., T. Shiroto, S.K., S.M., H.S.) and Department of Electronic Engineering, Graduate School of Engineering and Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering (H.T., H.H., H.K.), Tohoku University, Sendai, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000368:Aged; D000818:Animals; D001344:Autopsy; D016022:Case-Control Studies; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005838:Genotype; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D000069453:Ultrasonic Waves; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D019012:Integrin beta1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: caveolae; caveolin-1; integrins; myocardial infarction; myocardial ischemia