title: Acute hyperglycemia suppresses left ventricular diastolic function and inhibits autophagic flux in mice under prohypertrophic stimulation.
abstract: BACKGROUND
  Left ventricular (LV) dysfunction is closely associated with LV hypertrophy or diabetes, as well as insufficient autophagic flux. Acute or chronic hyperglycemia is a prognostic factor for patients with myocardial infarction. However, the effect of acute hyperglycemia on LV dysfunction of the hypertrophic heart and the mechanisms involved are still unclear. This study aimed to confirm our hypothesis that either acute or chronic hyperglycemia suppresses LV diastolic function and autophagic flux.
  
  
  METHODS
  The transverse aortic constriction (TAC) model and streptozocin-induced type 1 diabetic mellitus mice were used. LV function was evaluated with a Millar catheter. Autophagic levels and autophagic flux in the whole heart and cultured neonatal rat cardiomyocytes in response to hyperglycemia were examined by using western blotting of LC3B-II and P62. We also examined the effect of an autophagic inhibitor on LC3B-II and P62 protein expression and LC3 puncta.
  
  
  RESULTS
  In mice with TAC, we detected diastolic dysfunction as early as 30 min after TAC. This dysfunction was indicated by a greater LV end-diastolic pressure and the exponential time constant of LV relaxation, as well as a smaller maximum descending rate of LV pressure in comparison with sham group. Similar results were also obtained in mice with TAC for 2 weeks, in addition to increased insulin resistance. Acute hyperglycemic stress suppressed diastolic function in mice with myocardial hypertrophy, as evaluated by invasive LV hemodynamic monitoring. Mice with chronic hyperglycemia induced by streptozocin showed myocardial fibrosis and diastolic dysfunction. In high glucose-treated cardiomyocytes and streptozocin-treated mice, peroxisome proliferator-activated receptor-γ coactivator 1α was downregulated, while P62 was upregulated. Autophagic flux was also significantly inhibited in response to high glucose exposure in angiotensin-II treated cardiomyocytes.
  
  
  CONCLUSIONS
  Acute hyperglycemia suppresses diastolic function, damages mitochondrial energy signaling, and inhibits autophagic flux in prohypertrophic factor-stimulated cardiomyocytes.
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.
authors.forename: Jiahe
authors.identifier: http://orcid.org/0000-0001-8410-4330
authors.initials: J
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China. cckk22@126.com.
authors.forename: Kai
authors.initials: K
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.
authors.forename: Huixin
authors.initials: H
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.
authors.forename: Yingxue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.
authors.forename: Hairuo
authors.initials: H
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.
authors.forename: Zhenhuan
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
authors.forename: Wangjun
authors.initials: W
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Bin
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.|Cardiovascular Division of the Department of Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China. liao18@msn.com.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
keywords: Acute hyperglycemia; Autophagic flux; Diastolic function; Myocardial hypertrophy