Acute hyperglycemia suppresses left ventricular diastolic function and inhibits autophagic flux in mice under prohypertrophic stimulation

Jiahe Xie; Kai Cui; Huixin Hao; Yingxue Zhang; Hairuo Lin; Zhenhuan Chen; Xiaobo Huang; Shiping Cao; Wangjun Liao; Jianping Bin; Masafumi Kitakaze; Yulin Liao

doi:10.1186/s12933-016-0452-z

Acute hyperglycemia suppresses left ventricular diastolic function and inhibits autophagic flux in mice under prohypertrophic stimulation

Cardiovasc Diabetol. 2016 Sep 22;15(1):136. doi: 10.1186/s12933-016-0452-z.

Authors

Jiahe Xie¹, Kai Cui², Huixin Hao¹, Yingxue Zhang¹, Hairuo Lin¹, Zhenhuan Chen¹, Xiaobo Huang¹, Shiping Cao¹, Wangjun Liao³, Jianping Bin¹, Masafumi Kitakaze^{1

4}, Yulin Liao⁵

Affiliations

¹ State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou avenue north, Guangzhou, 510515, China.
² 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.
³ Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
⁴ Cardiovascular Division of the Department of Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁵ 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.

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.

Keywords: Acute hyperglycemia; Autophagic flux; Diastolic function; Myocardial hypertrophy.