title: Inactivation of INK4a and ARF induces myocardial proliferation and improves cardiac repair following ischemia‑reperfusion.
abstract: The growth of the heart during mammalian embryonic development is primarily dependent on an increase in the number of cardiomyocytes (CM). However, shortly following birth, CMs cease proliferating and further growth of the myocardium is achieved via hypertrophic expansion of the existing CM population. The cyclin-dependent kinase inhibitor 2A (Cdkn2a) locus encodes overlapping genes for two tumor suppressor proteins, p16INK4a and p19 alternative reading frame (ARF). To determine whether decreased Cdkn2a gene expression results in improved cardiac regeneration in vitro and in vivo following cardiac injury, the proliferation of CMs isolated from Cdkn2a knockout (KO) and wild‑type (WT) mice in vitro and in vivo were evaluated following generation of ischemia reperfusion (IR) injury. The KO mice demonstrated enhanced CM proliferation not only in vitro, but also in vivo. Furthermore, heart function was improved and scar size was decreased in the KO mice compared with that of the WT mice. The results also indicated that microRNA (miR)‑1 and miR‑195 expression levels associated with cell proliferation were reduced following IR injury in KO mice compared with those of WT mice. These results suggested that the inactivation of INK4a and ARF stimulated CM proliferation and promoted cardiac repair.
authors.affiliation: Department of Cardiology, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Songtao
authors.initials: S
authors.lastname: An
authors.affiliation: Department of Cardiology, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cardiology, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Chuanyu
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Anesthesia, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Bingyu
authors.initials: B
authors.lastname: Qin
authors.affiliation: Department of Anesthesia, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Xianhui
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Anesthesia, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Fanmin
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Anesthesia, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qi
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016276:Ventricular Function / Q000235:genetics; D014945:Wound Healing / Q000235:genetics*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C569389:MIRN195a microRNA, mouse; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse