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

Inês Falcão-Pires, Giuseppina Palladini, Nádia Goņalves, Jolanda Van Der Velden, Daniel Moreira-Goņalves, Daniela Miranda-Silva, Francesco Salinaro, Walter J. Paulus, Hans W M Niessen, Stefano Perlini, Adelino F. Leite-Moreira

Research output: Contribution to journalArticle

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 lm, SHAM 18.2 ± 0.3 lm) and myofilament maximal force (BA 25.7 ± 3.6 kN/m 2, SHAM 18.6 ± 1.4 kN/m 2), Ca 2+ 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 (Ktr; 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 (s; BA 14.0 ± 0.9 ms, SHAM 12.9 ± 0.4 ms). Diabetes increased cardiomyocyte diameter, fibrosis (DM 21.4 ± 0.4 lm, 13.9 ± 1.8%, DB 20.6 ± 0.4 lm, 13.8 ± 0.8%, respectively), myofilament Ca 2+sensitivity (DM 5.57 ± 0.02, DB 5.57 ± 0.01), advanced glycation end-product deposition (DM 4.9 ± 0.6 score/mm 2, DB 5.1 ± 0.4 score/mm2, SHAM 2.1 ± 0.3 score/mm 2), and apoptosis, while decreasing Ktr (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 enddiastolic-pressure: DM 7.0 ± 1.2 mmHg, DB 6.7 ± 0.7 mmHg, SHAM 5.3 ± 0.4 mmHg, steeper end-diastolicpressure- 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 diabeticbanded animals.

Original languageEnglish
Pages (from-to)801-814
Number of pages14
JournalBasic Research in Cardiology
Volume106
Issue number5
DOIs
Publication statusPublished - Sep 2011

Fingerprint

Diabetes Mellitus
Pressure
Myofibrils
Matrix Metalloproteinases
Tissue Inhibitor of Metalloproteinase-1
Phosphorylation
Cardiac Myocytes
Extracellular Matrix
Fibrosis
salicylhydroxamic acid
Diastolic Heart Failure
Lung
Advanced Glycosylation End Products
Streptozocin
Body Weight
Insulin
Apoptosis
Blood Pressure
Phenotype
Kidney

Keywords

  • Diabetes mellitus
  • Diastolic function
  • Hypertrophy
  • Myocardial stiffness
  • Pressure-overload
  • Relaxation

ASJC Scopus subject areas

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

Cite this

Falcão-Pires, I., Palladini, G., Goņalves, N., Van Der Velden, J., Moreira-Goņalves, D., Miranda-Silva, D., ... Leite-Moreira, A. F. (2011). Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload. Basic Research in Cardiology, 106(5), 801-814. https://doi.org/10.1007/s00395-011-0184-x

Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload. / Falcão-Pires, Inês; Palladini, Giuseppina; Goņalves, Nádia; Van Der Velden, Jolanda; Moreira-Goņalves, Daniel; Miranda-Silva, Daniela; Salinaro, Francesco; Paulus, Walter J.; Niessen, Hans W M; Perlini, Stefano; Leite-Moreira, Adelino F.

In: Basic Research in Cardiology, Vol. 106, No. 5, 09.2011, p. 801-814.

Research output: Contribution to journalArticle

Falcão-Pires, I, Palladini, G, Goņalves, N, Van Der Velden, J, Moreira-Goņalves, D, Miranda-Silva, D, Salinaro, F, Paulus, WJ, Niessen, HWM, Perlini, S & Leite-Moreira, AF 2011, 'Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload', Basic Research in Cardiology, vol. 106, no. 5, pp. 801-814. https://doi.org/10.1007/s00395-011-0184-x
Falcão-Pires I, Palladini G, Goņalves N, Van Der Velden J, Moreira-Goņalves D, Miranda-Silva D et al. Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload. Basic Research in Cardiology. 2011 Sep;106(5):801-814. https://doi.org/10.1007/s00395-011-0184-x
Falcão-Pires, Inês ; Palladini, Giuseppina ; Goņalves, Nádia ; Van Der Velden, Jolanda ; Moreira-Goņalves, Daniel ; Miranda-Silva, Daniela ; Salinaro, Francesco ; Paulus, Walter J. ; Niessen, Hans W M ; Perlini, Stefano ; Leite-Moreira, Adelino F. / Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload. In: Basic Research in Cardiology. 2011 ; Vol. 106, No. 5. pp. 801-814.
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T1 - Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload

AU - Falcão-Pires, Inês

AU - Palladini, Giuseppina

AU - Goņalves, Nádia

AU - Van Der Velden, Jolanda

AU - Moreira-Goņalves, Daniel

AU - Miranda-Silva, Daniela

AU - Salinaro, Francesco

AU - Paulus, Walter J.

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N2 - 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 lm, SHAM 18.2 ± 0.3 lm) and myofilament maximal force (BA 25.7 ± 3.6 kN/m 2, SHAM 18.6 ± 1.4 kN/m 2), Ca 2+ 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 (Ktr; 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 (s; BA 14.0 ± 0.9 ms, SHAM 12.9 ± 0.4 ms). Diabetes increased cardiomyocyte diameter, fibrosis (DM 21.4 ± 0.4 lm, 13.9 ± 1.8%, DB 20.6 ± 0.4 lm, 13.8 ± 0.8%, respectively), myofilament Ca 2+sensitivity (DM 5.57 ± 0.02, DB 5.57 ± 0.01), advanced glycation end-product deposition (DM 4.9 ± 0.6 score/mm 2, DB 5.1 ± 0.4 score/mm2, SHAM 2.1 ± 0.3 score/mm 2), and apoptosis, while decreasing Ktr (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 enddiastolic-pressure: DM 7.0 ± 1.2 mmHg, DB 6.7 ± 0.7 mmHg, SHAM 5.3 ± 0.4 mmHg, steeper end-diastolicpressure- 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 diabeticbanded animals.

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KW - Diabetes mellitus

KW - Diastolic function

KW - Hypertrophy

KW - Myocardial stiffness

KW - Pressure-overload

KW - Relaxation

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