The roles of MMP-2/TIMP-2 in extracellular matrix remodelling in the hearts of STZ-induced diabetic rats

Li, Qian; Sun, Song; Wang, Yi; Yongjie, Tian; Liu, Minghua

doi:10.2143/ac.62.5.2023412

Cited by 31 publications

(17 citation statements)

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“…On the other hand, the increased expression of pro-fibrotic factors, such as PAI-1 and ECM accumulation is consistent with DM-induced nephropathy and vasculopathy [17], [42]. Similarly, other groups report an imbalance between MMP and TIMP levels that lead to increased synthesis and accumulation of matrix proteins in the heart and kidneys of experimental models of DM [15], [16]. Plasma and urine samples from human diabetic patients show marked increases in MMP and TIMP concentrations, reflecting abnormal ECM turnover [43], [44].…”

Section: Discussionmentioning

confidence: 59%

“…A balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) is thought to play a central role in vessel remodeling, and an imbalance between MMPs and TIMPs may lead to excess ECM accumulation or degradation [13], [14]. For example, diabetic nephropathy and cardiomyopathy involves excessive ECM deposition due to a decrease in the MMP/TIMP ratio [15], [16]. The pro-fibrotic plasminogen activator inhibitor-1 (PAI-1) is increased in DM, insulin resistance, and hypertension [17].…”

Section: Introductionmentioning

confidence: 99%

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Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

et al. 2011

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ObjectiveResistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice.MethodsStructural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively.ResultsBlood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling.ConclusionsThese data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

et al. 2011

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“…Their presence reflects a dysregulation in matrix metabolism that is indicative of an ECM imbalance between MMP-2-mediated collagen degradation and TIMP-2-mediated MMP inhibition. The resulting outcome that was reported was an increase in matrix protein synthesis and accumulation similar to T2DM [51]. This observation offers a mechanism found in diabetic animals in which impaired collagen turnover contributes to increased matrix deposition and accumulation.…”

Section: Discussionmentioning

confidence: 59%

Cardiac Fibroblast-Dependent Extracellular Matrix Accumulation Is Associated with Diastolic Stiffness in Type 2 Diabetes

et al. 2013

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Cardiovascular complications are a leading cause of death in patients with type 2 diabetes mellitus (T2DM). Diastolic dysfunction is one of the earliest manifestations of diabetes-induced changes in left ventricular (LV) function, and results from a reduced rate of relaxation and increased stiffness. The mechanisms responsible for increased stiffness are not completely understood. Chronic hyperglycemia, advanced glycation endproducts (AGEs), and increased levels of proinflammatory and profibrotic cytokines are molecular pathways known to be involved in regulating extracellular matrix (ECM) synthesis and accumulation resulting in increased LV diastolic stiffness. Experiments were conducted using a genetically-induced mouse model of T2DM generated by a point mutation in the leptin receptor resulting in nonfunctional leptin receptors (db/db murine model). This study correlated changes in LV ECM and stiffness with alterations in basal activation of signaling cascades and expression of profibrotic markers within primary cultures of cardiac fibroblasts from diabetic (db/db) mice with nondiabetic (db/wt) littermates as controls. Primary cultures of cardiac fibrobroblasts were maintained in 25 mM glucose (hyperglycemic-HG; diabetic db/db) media or 5 mM glucose (normoglycemic-NG, nondiabetic db/wt) media. The cells then underwent a 24-hour exposure to their opposite (NG; diabetic db/db) media or 5 mM glucose (HG, nondiabetic db/wt) media. Protein analysis demonstrated significantly increased expression of type I collagen, TIMP-2, TGF-β, PAI-1 and RAGE in diabetic db/db cells as compared to nondiabetic db/wt, independent of glucose media concentration. This pattern of protein expression was associated with increased LV collagen accumulation, myocardial stiffness and LV diastolic dysfunction. Isolated diabetic db/db fibroblasts were phenotypically distinct from nondiabetic db/wt fibroblasts and exhibited a profibrotic phenotype in normoglycemic conditions.

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“…Indeed, Li et al [24] had previously shown that total collagen content correlated negatively with the activity and expression of MMP-2 and correlated positively with TIMP-1 expression in the myocardium of diabetic rats.…”

Section: Effects Of Diabetes Mellitusmentioning

confidence: 96%

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

et al. 2011

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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 (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 (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/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 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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The roles of MMP-2/TIMP-2 in extracellular matrix remodelling in the hearts of STZ-induced diabetic rats

Cited by 31 publications

References 0 publications

Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

Cardiac Fibroblast-Dependent Extracellular Matrix Accumulation Is Associated with Diastolic Stiffness in Type 2 Diabetes

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

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