title: Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload.
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/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.
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Falcão-Pires
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Palladini
authors.forename: Nádia
authors.initials: N
authors.lastname: Gonçalves
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.forename: Daniel
authors.initials: D
authors.lastname: Moreira-Gonçalves
authors.forename: Daniela
authors.initials: D
authors.lastname: Miranda-Silva
authors.forename: Francesco
authors.initials: F
authors.lastname: Salinaro
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.forename: Stefano
authors.initials: S
authors.lastname: Perlini
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000502:physiology; D054144:Heart Failure, Diastolic / Q000503:physiopathology*; D006352:Heart Ventricles / Q000473:pathology; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology*; D007328:Insulin / Q000502:physiology; D008297:Male; D009210:Myofibrils / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000009:adverse effects
chemical_list: D007328:Insulin; D013311:Streptozocin