https://doi.org/10.1007/s00392-025-02625-4
1Kath. Klinikum Bochum Institut für Forschung und Lehre (IFL), St. Josef Hospital Bochum, Deutschland; 2Ruhr-Universität Bochum Abteilung für Zelluläre und Translationale Physiologie Bochum, Deutschland; 3Klinikum der Ruhr-Universität Bochum Medizinische Klinik II, Kardiologie Bochum, Deutschland; 4Academic Medical Center University of Amsterdam Department of Cardiology Amsterdam, Niederlande; 5Kath. Klinikum Bochum Cellular Physiology Bochum, Deutschland
Introduction and Aims:
Heart Failure with Preserved Ejection Fraction (HFpEF) affects 45% of patients with Type 2 Diabetes Mellitus (T2DM), with key contributors including inflammation, oxidative stress, insulin resistance, and lipotoxicity. This study aims to examine inflammation-induced oxidative alterations in cardiac proteins, particularly protein kinases and myofilament proteins, in HFpEF-T2DM patients, potentially unveiling novel treatment targets.
Methods and Results:
Human heart biopsies from non-failing donors (CTRL), HFpEF-nonDM, and HFpEF-DM groups (12 samples each) were analyzed for protein kinase oxidation using Western Blot (WB) under reducing conditions. Results demonstrated increased dimer and polymer formation of Calcium Calmodulin-dependent kinase II (CaMKII) and protein Kinase G (PKG) in HFpEF-DM compared to HFpEF-nonDM and CTRL groups. In contrast, the monomeric (non-oxidized) form of CaMKII was elevated in CTRL. Validation by diagonal gel electrophoresis confirmed intrachain disulfide bridges in CaMKII and PKG in HFpEF-DM and HFpEF-nonDM, which were absent in the CTRL group. Additionally, inflammatory mediators and oxidative stress markers were significantly elevated in HFpEF-DM relative to HFpEF-nonDM.
Regarding cardiomyocyte functionality, passive stiffness was markedly higher in HFpEF-DM than in HFpEF-nonDM and reversible with PKG and CaMKII treatments. Oxidation not only affected kinases like PKG and CaMKII, contributing to increased cardiomyocyte stiffness but also myofilament proteins oxidation. Specifically, MyBPC oxidation was higher in HFpEF-DM compared to HFpEF-nonDM and CTRL groups, although Troponin I oxidation remained consistent across all groups.
Conclusion:
Our findings indicate that elevated inflammation and oxidative stress in HFpEF-DM lead to oxidative modifications of protein kinases (PKG, CaMKII) and myofilament proteins (MyBPC), contributing to cardiomyocyte stiffness. These oxidative modifications represent a key mechanism underlying HFpEF in T2DM, suggesting that targeting oxidative pathways and kinase modulation could provide therapeutic benefits for HFpEF patients with diabetes.
Keywords: heart failure, diabetics mellitus, inflammation, oxidative stress