Clinical impact of myocardial mTORC1 activation in nonischemic dilated cardiomyopathy

Autor: Atsushi Mochizuki, Takayuki Miki, Shinya Shimoshige, Satoshi Yuda, Takefumi Fujito, Tetsuji Miura, Makoto Ogasawara, Masaya Tanno, Kazufumi Tsuchihashi, Toshiyuki Yano, Atsuko Muranaka, Akiyoshi Hashimoto
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Biopsy
Gene Expression
Angiotensin-Converting Enzyme Inhibitors
030204 cardiovascular system & hematology
0302 clinical medicine
Fibrosis
Brugada Syndrome
Brugada syndrome
Ejection fraction
medicine.diagnostic_test
TOR Serine-Threonine Kinases
Ribosomal Protein S6 Kinases
70-kDa
Dilated cardiomyopathy
Middle Aged
Disease Progression
Cardiology
Female
biological phenomena
cell phenomena
and immunity
Cardiology and Cardiovascular Medicine
Adult
Cardiomyopathy
Dilated
medicine.medical_specialty
Heart Ventricles
Mechanistic Target of Rapamycin Complex 1
Angiotensin Receptor Antagonists
03 medical and health sciences
Internal medicine
medicine
Animals
Humans
Molecular Biology
Endocardium
Retrospective Studies
Heart Failure
business.industry
Myocardium
Ribosomal Protein S6 Kinases
Phosphoproteins
medicine.disease
Survival Analysis
Enzyme Activation
030104 developmental biology
Multiprotein Complexes
Heart failure
Myocardial fibrosis
business
Zdroj: Journal of Molecular and Cellular Cardiology. 91:6-9
ISSN: 0022-2828
DOI: 10.1016/j.yjmcc.2015.12.022
Popis: Activity of mTOR complex 1 (mTORC1) has been shown to be up-regulated in animal models of heart failure. Here, we investigated the change and role of mTORC1 in human nonischemic dilated cardiomyopathy (NICM).Endomyocardial biopsy specimens were obtained from patients with NICM (n=52) and from Brugada syndrome patients with normal LVEF as controls (n=10). The specimens were stained for phospho-ribosomal protein S6 (p-Rps6) and phospho-p70S6K (p-p70S6K), and the area with p-Rps6 signal was used as an index of mTORC1 activity. Using median mTORC1 activity, patients were divided into a high mTORC1 activity (H-mTOR) group and a low mTORC1 activity (L-mTOR) group.The ratio of p-Rps6-positive area in biopsy samples was 10-fold larger in patients with NICM than in controls (2.0±2.2% vs. 0.2±0.2%, p0.01). p-p70S6K signal level was higher in the H-mTOR group than in the L-mTOR group. The proportion of patients with a family history of cardiomyopathy was higher and the proportion of patients on ACE inhibitors or angiotensin receptor blockers was lower in the H-mTOR group than in the L-mTOR group. The p-Rps6-positive area was correlated with extent of myocardial fibrosis (r=0.46, p0.01). The cardiac event-free survival rate during a 5-year follow-up period tended to be lower in the H-mTOR group than in the L-mTOR group (52.9% vs. 81.6%, P=0.10).Aberrant activation of mTORC1 in cardiomyocytes was associated with myocardial fibrosis and a trend for worse prognosis in patients with NICM, indicating that persistently activated mTORC1 contributes to progression of human heart failure.
Databáze: OpenAIRE
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