Impact of hyperinsulinemia and hyperglycemia on valvular interstitial cells – A link between aortic heart valve degeneration and type 2 diabetes

Selig, Jessica Isabel; Ouwens, D.M.; Raschke, Silja; Thoresen, G. Hege; Fischer, Jens W.; Lichtenberg, Artur; Akhyari, Payam; Barth, Mareike

doi:10.1016/j.bbadis.2019.05.019

Cited by 20 publications

(35 citation statements)

References 71 publications

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“…There are few studies regarding the effects of HG on osteogenic pathways and molecules associated with aortic valve calcification. Recently, osteopontin gene expression and calcium deposition were not found modified by HG in VIC cultured in 2D system, 21 differences that underline VIC response to 3D culture.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, our group showed that HG induces enhanced monocyte adhesion to VEC via a mechanism involving the cell adhesion molecules: ICAM‐1, VCAM‐1 and CD 18 20 . Recently, using a 2D culture, it was found that VIC from sheep origin do not show morphological changes and do not acquire an osteogenic phenotype in hyperinsulinaemia or hyperglycaemia 21 …”

Section: Introductionmentioning

confidence: 99%

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Molecular mechanisms involved in high glucose‐induced valve calcification in a 3D valve model with human valvular cells

Vadana¹,

Cecoltan²,

Ciortan³

et al. 2020

J Cellular Molecular Medi

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Calcific aortic valve disease (CAVD)—the most common valvular heart disease—is accelerated in diabetes and has no pharmacotherapy. Although it is known that early CAVD is associated with inflammation and osteogenesis, the molecular mechanisms involved in diabetes‐associated CAVD still need to be uncovered. In this context, we have developed a 3D construct based on gelatin populated with human valvular endothelial cells (VEC) and valvular interstitial cells (VIC) and evaluated the effect of high glucose (HG) concentration on osteogenic molecules expression and on calcification mechanisms. First, we characterized the 3D model and assessed VIC remodelling properties at different time‐points. Then, we exposed it to normal glucose (NG) or high glucose (HG) for 7, 14 and 21 days after which the cells were isolated, separated and investigated individually. Our results showed that encapsulated VIC actively remodel the hydrogel, as demonstrated by an increased expression of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs). Moreover, exposure of the construct to HG triggered bone morphogenetic protein (BMP) and TGF‐β signalling pathways, up‐regulating expression of osteogenic molecules—BMP‐2/‐4, osteocalcin, osteopontin, SMADs and Runt‐related transcription factor (Runx‐2)—and increased calcium deposits in an osteogenic environment. These findings underline the potential of the developed 3D model as a suitable system to investigate the mechanisms of human CAVD and may help to better understand the calcification mechanisms in CAVD associated to diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms involved in high glucose‐induced valve calcification in a 3D valve model with human valvular cells

Vadana¹,

Cecoltan²,

Ciortan³

et al. 2020

J Cellular Molecular Medi

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“…ATP production was converted to mitochondrial ATP production rate by the formula: mitoATP production rate = ATP production × 2 (pmol O/pmol O 2 ) × P/O (pmol ATP/pmol O), whereby P/O was set at a validated value of 2.75 [15]. The conversion of ECAR into proton efflux rate (PER) [15,16,17] was performed to calculate the glycolytic ATP production rate. The glycolytic ATP production rate is equivalent to the glycolytic proton efflux rate (glycoPER), which, in turn, is obtained by subtracting mitochondrial PER from total PER as described [17].…”

Section: Methodsmentioning

confidence: 99%

“…The conversion of ECAR into proton efflux rate (PER) [15,16,17] was performed to calculate the glycolytic ATP production rate. The glycolytic ATP production rate is equivalent to the glycolytic proton efflux rate (glycoPER), which, in turn, is obtained by subtracting mitochondrial PER from total PER as described [17].…”

Section: Methodsmentioning

confidence: 99%

Increased Glycolysis and Higher Lactate Production in Hyperglycemic Myotubes

Lund

Ouwens

Wettergreen

et al. 2019

Cells

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Previous studies have shown that chronic hyperglycemia impairs glucose and fatty acid oxidation in cultured human myotubes. To further study the hyperglycemia-induced suppression of oxidation, lactate oxidation, mitochondrial function and glycolytic rate were evaluated. Further, we examined the intracellular content of reactive oxygen species (ROS), production of lactate and conducted pathway-ANOVA analysis on microarray data. In addition, the roles of the pentose phosphate pathway (PPP) and the hexosamine pathway were evaluated. Lactic acid oxidation was suppressed in hyperglycemic versus normoglycaemic myotubes. No changes in mitochondrial function or ROS concentration were observed. Pathway-ANOVA analysis indicated several upregulated pathways in hyperglycemic cells, including glycolysis and PPP. Functional studies showed that glycolysis and lactate production were higher in hyperglycemic than normoglycaemic cells. However, there were no indications of involvement of PPP or the hexosamine pathway. In conclusion, hyperglycemia reduced substrate oxidation while increasing glycolysis and lactate production in cultured human myotubes.

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“…The insulin concentrations used in this study were extrapolated from plasma insulin concentrations of people with hyperinsulinemia/insulin resistance [31,32]. Insulin has been shown to have a pro-proliferative effect on several cell types, including mesenchymal stem/progenitor cells [33][34][35][36][37][38]. Insulin and IGF-I ligands and their respective receptors share marked similarities in their signaling properties in eukaryotic cells [22].…”

Section: Discussionmentioning

confidence: 99%

Insulin Enhances the In Vitro Osteogenic Capacity of Flexor Tendon-Derived Progenitor Cells

Durgam

Altmann

Coughlin

et al. 2019

Stem Cells International

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There is increased incidence of tendon disorders and decreased tendon healing capacity in people with diabetes mellitus (DM). Recent studies have also suggested pathological ossification in repair tendon of people with DM. Therefore, the objective of this study is to investigate the effects of insulin supplementation, an important pathophysiologic stimulus of DM, on tendon progenitor cell (TPC) proliferation and in vitro osteogenic capacity. Passage 3 TPCs were isolated from collagenase-digested, equine superficial digital flexor tendons. TPC proliferation was measured via MTT assay after 3 days of monolayer culture in medium supplemented with 0, 0.007, 0.07, and 0.7 nM insulin. In vitro osteogenic capacity of TPCs (Alizarin Red staining, osteogenic mRNA expression, and alkaline phosphatase bioactivity) was assessed with 0, 0.07, and 0.7 nM insulin-supplemented osteogenic induction medium. Insulin (0.7 nM) significantly increased TPC proliferation after 3 days of monolayer culture. Alizarin Red staining of insulin-treated TPC osteogenic cultures demonstrated robust cell aggregation and mineralized matrix secretion, in a dose-dependent manner. Runx2, alkaline phosphatase, and Osteonectin mRNA and alkaline phosphatase bioactivity of insulin-treated TPC cultures were significantly higher at day 14 of osteogenesis compared to untreated controls. Addition of picropodophyllin (PPP), a selective IGF-I receptor inhibitor, mitigated the increased osteogenic capacity of TPCs, indicating that IGF-I signaling plays an important role. Our findings indicate that hyperinsulinemia may alter TPC phenotype and subsequently impact the quality of repair tendon tissue.

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Impact of hyperinsulinemia and hyperglycemia on valvular interstitial cells – A link between aortic heart valve degeneration and type 2 diabetes

Cited by 20 publications

References 71 publications

Molecular mechanisms involved in high glucose‐induced valve calcification in a 3D valve model with human valvular cells

Molecular mechanisms involved in high glucose‐induced valve calcification in a 3D valve model with human valvular cells

Increased Glycolysis and Higher Lactate Production in Hyperglycemic Myotubes

Insulin Enhances the In Vitro Osteogenic Capacity of Flexor Tendon-Derived Progenitor Cells

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