Diastolic dysfunction is initiated by cardiomyocyte impairment ahead of endothelial dysfunction due to increased oxidative stress and inflammation in an experimental prediabetes model

Mark T. Waddingham, Takashi Sonobe, Hirotsugu Tsuchimochi, Amanda J. Edgley, Vijayakumar Sukumaran, Yi Ching Chen, Sarabjit S. Hansra, Daryl O. Schwenke, Keiji Umetani, Kohki Aoyama, Naoto Yagi, Darren J. Kelly, Shahrooz Gaderi, Melissa Herwig, Detmar Kolijn, Andreas Mügge, Walter J. Paulus, Takeshi Ogo, Mikiyasu Shirai, Nazha HamdaniJames T. Pearson

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Coronary microvessel endothelial dysfunction and nitric oxide (NO) depletion contribute to elevated passive tension of cardiomyocytes, diastolic dysfunction and predispose the heart to heart failure with preserved ejection fraction. We examined if diastolic dysfunction at the level of the cardiomyocytes precedes coronary endothelial dysfunction in prediabetes. Further, we determined if myofilaments other than titin contribute to impairment. Utilizing synchrotron microangiography we found young prediabetic male rats showed preserved dilator responses to acetylcholine in microvessels. Utilizing synchrotron X-ray diffraction we show that cardiac relaxation and cross-bridge dynamics are impaired by myosin head displacement from actin filaments particularly in the inner myocardium. We reveal that increased PKC activity and mitochondrial oxidative stress in cardiomyocytes contributes to rho-kinase mediated impairment of myosin head extension to actin filaments, depression of soluble guanylyl cyclase/PKG activity and consequently stiffening of titin in prediabetes ahead of coronary endothelial dysfunction.

Original languageEnglish
Pages (from-to)119-131
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume137
DOIs
Publication statusPublished - 1 Dec 2019

Keywords

  • Actin-myosin
  • Diastolic dysfunction
  • Inflammation
  • Oxidative stress
  • Prediabetes
  • Protein kinase G
  • Rho-kinase
  • Soluble guanylyl cyclase
  • Titin

Cite this

Waddingham, M. T., Sonobe, T., Tsuchimochi, H., Edgley, A. J., Sukumaran, V., Chen, Y. C., Hansra, S. S., Schwenke, D. O., Umetani, K., Aoyama, K., Yagi, N., Kelly, D. J., Gaderi, S., Herwig, M., Kolijn, D., Mügge, A., Paulus, W. J., Ogo, T., Shirai, M., ... Pearson, J. T. (2019). Diastolic dysfunction is initiated by cardiomyocyte impairment ahead of endothelial dysfunction due to increased oxidative stress and inflammation in an experimental prediabetes model. Journal of Molecular and Cellular Cardiology, 137, 119-131. https://doi.org/10.1016/j.yjmcc.2019.10.005