Lin28a protects against postinfarction myocardial remodeling and dysfunction through Sirt1 activation and autophagy enhancement.
BACKGROUND
Myocardial remodeling and cardiac dysfunction prevention may represent a therapeutic approach to reduce mortality in patients with myocardial infarction (MI). We investigated the effects of Lin28a in experimental MI models, as well as the mechanisms underlying these effects.


METHODS
Left anterior descending (LAD) coronary artery ligation was used to construct an MI-induced injury model. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of Lin28a against MI-induced injury.


RESULTS
Lin28a significantly inhibited left ventricular remodeling and cardiac dysfunction after MI, as demonstrated via echocardiography and hemodynamic measurements. Lin28a reduced cardiac enzyme and inflammatory marker release in mice subjected to MI-induced injury. The mechanisms underlying the protective effects of Lin28a against MI-induced injury were associated with autophagy enhancements and apoptosis inhibition. Consistent with these findings, Lin28a knockdown aggravated cardiac remodeling and dysfunction after MI-induced injury. Lin28a knockdown also inhibited cardiomyocyte autophagy and increased cardiomyocyte apoptosis in mice subjected to MI-induced injury. Interestingly, Sirt1 knockdown abolished the protective effects of Lin28a against cardiac remodeling and dysfunction after MI, and Lin28a failed to increase the numbers of GFP-LC3-positive punctae and decrease aggresome and p62 accumulation in Sirt1-knockdown neonatal cardiomyocytes subjected to hypoxia-induced injury.


CONCLUSIONS
Lin28a inhibits cardiac remodeling, improves cardiac function, and reduces cardiac enzyme and inflammatory marker release after MI. Lin28a also up-regulates cardiomyocyte autophagy and inhibits cardiomyocyte apoptosis through Sirt1 activation.
Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Yuanyuan
Y
Hao
Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Qun
Q
Lu
Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Guodong
G
Yang
Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Shaanxi Key Laboratory of Molecular Cardiology (Xi'an Jiaotong University), Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Shaanxi 710061, China. Electronic address: 15289366123@163.com.
Aiqun
A
Ma
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D002316:Cardiotonic Agents / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000517:prevention & control; D020257:Ventricular Remodeling / Q000502:physiology
D002316:Cardiotonic Agents; C488352:Lin-28 protein, mouse; D016601:RNA-Binding Proteins; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
Apoptosis; Autophagy; Lin28a; MI; Myocardial infarction; Sirt1