title: Gene silencing of myofibrillogenesis regulator-1 by adenovirus-delivered small interfering RNA suppresses cardiac hypertrophy induced by angiotensin II in mice.
abstract: Our previous studies proved that myofibrillogenesis regulator (MR)-1 has a close relationship with cardiac hypertrophy induced by ANG II. In the present study, we developed a recombinant adenoviral vector (AdSiR-MR-1) driving small interfering (si)RNA against MR-1 to evaluate its effect on cardiac hypertrophy in vivo. Cardiac hypertrophy was induced by chronic ANG II infusion in mice; AdSiR-MR-1 was administered via the jugular vein through one bolus injection. Thirteen days after the injection, viral DNA was still detectable in the heart, validating the efficiency of gene transfer. Expression levels of MR-1 mRNA and protein were increased by 2.5-fold in the heart after ANG II infusion; AdSiR-control, which contained a scrambled siRNA sequence, had no effect on them. AdSiR-MR-1 treatment abolished the upregulation of MR-1 induced by ANG II. The silencing effect of AdSiR-MR-1 was observed in many other tissues, such as the liver, lung, and kidney, except skeletal muscle. ANG II-induced cardiac hypertrophy was suppressed in mice treated with AdSiR-MR-1, as determined by echocardiography. Morphological and immnohistochemical examinations revealed that interstitial cardiac fibrosis as well as infiltrating inflammatory cells were increased after ANG II infusion; AdSiR-MR-1 greatly ameliorated these disorders. In ANG II-infused mice, MR-1 silencing also blocked the upregulation of other genes related to cardiac hypertrophy or metabolism of the extracellular matrix. In summary, our results demonstrate the feasibility of MR-1 silencing in vivo and suggest that MR-1 could be a potential new target to treat cardiac hypertrophy induced by ANG II.
authors.affiliation: Key Laboratory of Antibiotic Biotechnology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Dai
authors.forename: Weiqing
authors.initials: W
authors.lastname: He
authors.forename: Guangdong
authors.initials: G
authors.lastname: Shang
authors.forename: Jiandong
authors.initials: J
authors.lastname: Jiang
authors.forename: Yiguang
authors.initials: Y
authors.lastname: Wang
authors.forename: Weijia
authors.initials: W
authors.lastname: Kong
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D034741:RNA, Small Interfering; C547209:myofibrillogenesis regulator-1, mouse; D000804:Angiotensin II; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2