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Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload

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Abstract

Chronic pressure-overload and diabetes mellitus are two frequent disorders affecting the heart. We aimed to characterize myocardial structural and functional changes induced by both conditions. Pressure-overload was established in Wistar-han male rats by supra-renal aortic banding. Six-weeks later, diabetes was induced by streptozotocin (65 mg/kg,ip), resulting in four groups: SHAM, banding (BA), diabetic (DM) and diabetic-banding (DB). Six-weeks later, pressure–volume loops were obtained and left ventricular samples were collected to evaluate alterations in insulin signalling pathways, extracellular matrix as well as myofilament function and phosphorylation. Pressure-overload increased cardiomyocyte diameter (BA 22.0 ± 0.4 μm, SHAM 18.2 ± 0.3 μm) and myofilament maximal force (BA 25.7 ± 3.6 kN/m2, SHAM 18.6 ± 1.4 kN/m2), Ca2+ sensitivity (BA 5.56 ± 0.02, SHAM 5.50 ± 0.02) as well as MyBP-C, Akt and Erk phosphorylation, while decreasing rate of force redevelopment (K tr; BA 14.9 ± 1.1 s−1, SHAM 25.2 ± 1.5 s−1). At the extracellular matrix level, fibrosis (BA 10.8 ± 0.9%, SHAM 5.3 ± 0.6%), pro-MMP-2 and MMP-9 activities increased and, in vivo, relaxation was impaired (τ; BA 14.0 ± 0.9 ms, SHAM 12.9 ± 0.4 ms). Diabetes increased cardiomyocyte diameter, fibrosis (DM 21.4 ± 0.4 μm, 13.9 ± 1.8%, DB 20.6 ± 0.4 μm, 13.8 ± 0.8%, respectively), myofilament Ca2+sensitivity (DM 5.57 ± 0.02, DB 5.57 ± 0.01), advanced glycation end-product deposition (DM 4.9 ± 0.6 score/mm2, DB 5.1 ± 0.4 score/mm2, SHAM 2.1 ± 0.3 score/mm2), and apoptosis, while decreasing K tr (DM 13.5 ± 1.9 s−1, DB 15.2 ± 1.4 s−1), Akt phosphorylation and MMP-9/TIMP-1 and MMP-1/TIMP-1 ratios. Diabetic hearts were stiffer (higher end-diastolic-pressure: DM 7.0 ± 1.2 mmHg, DB 6.7 ± 0.7 mmHg, SHAM 5.3 ± 0.4 mmHg, steeper end-diastolic-pressure–volume relation: DM 0.59 ± 0.18, DB 0.83 ± 0.17, SHAM 0.41 ± 0.10), and hypo-contractile (decreased end-systolic-pressure-volume-relation). DB animals presented further pulmonary congestion (Lungs/body-weight: DB 5.23 ± 0.21 g/kg, SHAM 3.80 ± 0.14 g/kg) as this group combined overload-induced relaxation abnormalities and diabetes-induced stiffness. Diabetes mellitus and pressure overload led to distinct diastolic dysfunction phenotypes: while diabetes promoted myocardial stiffening, pressure overload impaired relaxation. The association of these damages accelerates the progression of diastolic heart failure progression in diabetic-banded animals.

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Acknowledgments

The authors would like to thank Doctor José Magalhães and his group for kindly providing anti-Bax and anti-Bcl-2 antibodies. This work was supported by the Portuguese Foundation for Science and Technology (grant number PIC/IC/82943/2007) through the Cardiovascular R&D Unit (FCT nr. 51/94) and by the European Union Project FP7-HEALTH-2010: “MEDIA-Metabolic Road to Diastolic Heart Failure”. #HEALTH. 2010.2.4.2-4.

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Authors and Affiliations

  1. Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal

    Inês Falcão-Pires, Nádia Gonçalves, Daniel Moreira-Gonçalves, Daniela Miranda-Silva & Adelino F. Leite-Moreira

  2. Clinica Medica II, Fondazione IRCCS San Matteo, Università di Pavia, Pavia, Italy

    Giuseppina Palladini, Francesco Salinaro & Stefano Perlini

  3. Department of Physiology, Institute for Cardiovascular Research, Vrije University Medical Center Amsterdam, Amsterdam, The Netherlands

    Jolanda van der Velden & Walter J. Paulus

  4. Pathology and Surgery, Vrije University Medical Center, Amsterdam, The Netherlands

    Hans W. M. Niessen

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  1. Inês Falcão-Pires
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  2. Giuseppina Palladini
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  3. Nádia Gonçalves
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  4. Jolanda van der Velden
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  9. Hans W. M. Niessen
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  11. Adelino F. Leite-Moreira
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Correspondence to Adelino F. Leite-Moreira.

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Falcão-Pires, I., Palladini, G., Gonçalves, N. et al. Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload. Basic Res Cardiol 106, 801–814 (2011). https://doi.org/10.1007/s00395-011-0184-x

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