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

• Type: Article in International Scientific Journal
• Date: 2011

Authors

Falcão-Pires I (Author) FMUP; Palladini G (Author) Other; Gonçalves N (Author) FMUP; van der Velden J (Author) Other; Moreira-Gonçalves D (Author) Other; Miranda-Silva D (Author) Other; Salinaro F (Author) Other; Paulus WJ (Author) Other; Niessen HW (Author) Other; Perlini S (Author) Other; Leite-Moreira AF (Author) FMUP

Journal

Title: Basic Research in Cardiology

Vol. 106 No. 5

Pages: 801-814

ISSN: 0300-8428

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 50 Citations

Scopus - 52 Citations

Scientific classification

FOS: Medical and Health sciences > Other medical sciences

Other information

Authenticus ID: P-002-N91

DOI: 10.1007/s00395-011-0184-x

Resumo (PT): 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/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 (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 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/mm(2), SHAM 2.1 ± 0.3 score/mm(2)), 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.

Abstract (EN): 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 +/- A 0.4 mu m, SHAM 18.2 +/- A 0.3 mu m) and myofilament maximal force (BA 25.7 +/- A 3.6 kN/m(2), SHAM 18.6 +/- A 1.4 kN/m(2)), Ca2+ sensitivity (BA 5.56 +/- A 0.02, SHAM 5.50 +/- A 0.02) as well as MyBP-C, Akt and Erk phosphorylation, while decreasing rate of force redevelopment (K (tr); BA 14.9 +/- A 1.1 s(-1), SHAM 25.2 +/- A 1.5 s(-1)). At the extracellular matrix level, fibrosis (BA 10.8 +/- A 0.9%, SHAM 5.3 +/- A 0.6%), pro-MMP-2 and MMP-9 activities increased and, in vivo, relaxation was impaired (tau; BA 14.0 +/- A 0.9 ms, SHAM 12.9 +/- A 0.4 ms). Diabetes increased cardiomyocyte diameter, fibrosis (DM 21.4 +/- A 0.4 mu m, 13.9 +/- A 1.8%, DB 20.6 +/- A 0.4 mu m, 13.8 +/- A 0.8%, respectively), myofilament Ca(2+)sensitivity (DM 5.57 +/- A 0.02, DB 5.57 +/- A 0.01), advanced glycation end-product deposition (DM 4.9 +/- A 0.6 score/mm(2), DB 5.1 +/- A 0.4 score/mm(2), SHAM 2.1 +/- A 0.3 score/mm(2)), and apoptosis, while decreasing K (tr) (DM 13.5 +/- A 1.9 s(-1), DB 15.2 +/- A 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 +/- A 1.2 mmHg, DB 6.7 +/- A 0.7 mmHg, SHAM 5.3 +/- A 0.4 mmHg, steeper end-diastolic-pressure-volume relation: DM 0.59 +/- A 0.18, DB 0.83 +/- A 0.17, SHAM 0.41 +/- A 0.10), and hypo-contractile (decreased end-systolic-pressure-volume-relation). DB animals presented further pulmonary congestion (Lungs/body-weight: DB 5.23 +/- A 0.21 g/kg, SHAM 3.80 +/- A 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14