Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress

Gábor Koncsos, Zoltán V. Varga, Tamás Baranyai, Kerstin Boengler, Susanne Rohrbach, Ling Li, Klaus Dieter Schlüter, Rolf Schreckenberg, Tamás Radovits, Attila Oláh, Csaba Mátyás, Árpád Lux, Mahmoud Al-Khrasani, Tímea Komlódi, Nóra Bukosza, Domokos Máthé, László Deres, Monika Barteková, Tomáš Rajtík, Adriana AdameováKrisztián Szigeti, Péter Hamar, Zsuzsanna Helyes, László Trette, P. Pacher, Béla Merkely, Zoltán Giricz, Rainer Schulz, Péter Ferdinandy

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24 Citations (Scopus)

Abstract

Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4. High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto-and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria.

Original languageEnglish
Pages (from-to)H927-H943
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume311
Issue number4
DOIs
Publication statusPublished - jan. 1 2016

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ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Koncsos, G., Varga, Z. V., Baranyai, T., Boengler, K., Rohrbach, S., Li, L., Schlüter, K. D., Schreckenberg, R., Radovits, T., Oláh, A., Mátyás, C., Lux, Á., Al-Khrasani, M., Komlódi, T., Bukosza, N., Máthé, D., Deres, L., Barteková, M., Rajtík, T., ... Ferdinandy, P. (2016). Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress. American Journal of Physiology - Heart and Circulatory Physiology, 311(4), H927-H943. https://doi.org/10.1152/ajpheart.00049.2016