I(f) current channel inhibitor (ivabradine) deserves cardioprotective effect via down-regulating the expression of matrix metalloproteinase (MMP)-2 and attenuating apoptosis in diabetic mice

Chen, Shao‐Liang; Hu, Zuo‐Ying; Zuo, Guang-Feng; Li, Minghui; Li, Bin

doi:10.1186/1471-2261-14-150

Cited by 21 publications

(15 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All these functions subsequently resulted in cardiac remodeling and heart failure. In accordance with our results, animal studies also showed that MMP-2 expression and activity was increased in the diabetic heart (3,4). Therefore, we suggest that high glucose levels up-regulate the expression of MMP-2, which further promotes ECM degradation, increased HCF migration and proliferation, finally resulting in fibrosis and DCM.…”

Section: Discussionsupporting

confidence: 90%

“…Among the MMPs, MMP-2 and MMP-9 are the major gelatinases that play an important role in the development of DCM by degrading the ECM (2). MMP-2 expression is higher in a diabetic heart (3,4). Moreover, dysregulation of MMP proteins and their endogenous inhibitor, namely, tissue inhibitor of metalloproteinase (TIMP), has been observed in the diabetic heart, suggesting that MMPs/TIMPs are involved in DCM.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts

et al. 2018

View full text Add to dashboard Cite

Cardiac fibrosis is a major pathological manifestation of diabetic cardiomyopathy (DCM), which leads to cardiac remodeling, dilated cardiomyopathy and congestive heart failure. Human cardiac fibroblasts (HCF) constitute the predominant cell type in the heart and matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are also involved in cardiac fibrosis. However, it is unclear whether high glucose levels affect the expression of MMPs and TIMPs in HCF. Sodium‑glucose cotransporter (SGLT) inhibitors have been developed as therapeutic agents and the anti‑DCM effect of SGLT inhibitors has been demonstrated by previous studies. However, whether SLGT inhibitors protect the diabetic heart by directly inhibiting the SGLTs in HCF in addition to lowering the blood glucose levels, has not yet been determined. In the present study, increased MMP‑2 expression was noted in HCFs in response to high glucose levels, which may be reversed by phlorizin (inhibits both SGLT1 and SGLT2), but not dapagliflozin (inhibits SGLT2). In addition, SGLT1 was revealed to be present in the HCFs and high glucose level was demonstrated to increase SGLT1 expression, which may be attenuated by phlorizin. Therefore it was concluded that high glucose levels induced MMP‑2 expression in the HCFs, potentially by upregulating SGLT1. SGLT1 inhibition may be a novel strategy for the treatment of DCM.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Increased cardiomyocyte apoptosis was a predominant cause of loss of contractile tissue, cardiac remodeling and, eventually, dysfunction [8]. Our previous study showed that inhibition of cardiomyocyte apoptosis improved cardiac function in diabetic mice [9]. Thus, anti-apoptosis is a potential treatment strategy for DCM.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Ren

Zuo

et al. 2016

PLoS ONE

Self Cite

View full text Add to dashboard Cite

Recent studies reported that atorvastatin (ATOR) alleviated progression of experimental diabetic cardiomyopathy (DCM), possibly by protecting against apoptosis. However, the underlying mechanisms of this protective effect remain unclear. Therefore, our study investigated the role of the glycogen synthase kinase (GSK)-3β-protein phosphatase 2A(PP2A)-NF-κB signaling pathway in the anti-apoptotic and cardioprotective effects of ATOR on cardiomyocytes cultured in high glucose (HG) and in DCM. Our results showed that, in HG-cultured cardiomyocytes, phosphorylation of GSK-3β was decreased, while that of the PP2A catalytic subunit C (PP2Ac) and IKK/IкBα was increased, followed by NF-кB nuclear translocation and apoptosis. IKK/IкBα phosphorylation and NF-кB nuclear translocation were also increased by treatment of cells with okadaic acid (OA), a selective PP2A inhibitor, or by silencing PP2Ac expression. The opposite results were obtained by silencing GSK-3β expression, which resulted in PP2Ac activation. Furthermore, IKK/IкBα phosphorylation and NF-кB nuclear translocation were markedly inhibited and apoptosis attenuated in cells treated with ATOR. These effects occurred through inactivation of GSK-3β and subsequent activation of PP2Ac. They were abolished by treatment of cells with OA or PP2Ac siRNA. In mice with type 1 diabetes mellitus, treatment with ATOR, at 10 mg-kg−1-d−1, significantly suppressed GSK-3β activation, IKK/IкBα phosphorylation, NF-кB nuclear translocation and caspase-3 activation, while also activating PP2Ac. Finally, improvements in histological abnormalities, fibrosis, apoptosis and cardiac dysfunction were observed in diabetic mice treated with ATOR. These findings demonstrated that ATOR protected against HG-induced apoptosis in cardiomyocytes and alleviated experimental DCM by regulating the GSK-3β-PP2A-NF-κB signaling pathway.

show abstract

“…According to our theory, this early MMP-2 downregulation is reverted during the progression of diabetic cardiomyopathy, causing an increased deposition of degraded collagen and the development of the fibrosis and apoptotic cell death. Indeed, at this late stage, the pharmacological inhibition of this process by ivabradine determines a normalization of MMP-2 activation, the prevention of apoptosis, and an improvement of cardiac dysfunction [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Role of TSPO/VDAC1 Upregulation and Matrix Metalloproteinase-2 Localization in the Dysfunctional Myocardium of Hyperglycaemic Rats

Gliozzi

Scarano

Musolino

et al. 2020

IJMS

View full text Add to dashboard Cite

Clinical management of diabetic cardiomyopathy represents an unmet need owing to insufficient knowledge about the molecular mechanisms underlying the dysfunctional heart. The aim of this work is to better clarify the role of matrix metalloproteinase 2 (MMP-2) isoforms and of translocator protein (TSPO)/voltage-dependent anion-selective channel 1 (VDAC1) modulation in the development of hyperglycaemia-induced myocardial injury. Hyperglycaemia was induced in Sprague-Dawley rats through a streptozocin injection (35 mg/Kg, i.p.). After 60 days, cardiac function was analysed by echocardiography. Nicotinamide Adenine Dinucleotide Phosphate NADPH oxidase and TSPO expression was assessed by immunohistochemistry. MMP-2 activity was detected by zymography. Superoxide anion production was estimated by MitoSOX™ staining. Voltage-dependent anion-selective channel 1 (VDAC-1), B-cell lymphoma 2 (Bcl-2), and cytochrome C expression was assessed by Western blot. Hyperglycaemic rats displayed cardiac dysfunction; this response was characterized by an overexpression of NADPH oxidase, accompanied by an increase of superoxide anion production. Under hyperglycaemia, increased expression of TSPO and VDAC1 was detected. MMP-2 downregulated activity occurred under hyperglycemia and this profile of activation was accompanied by the translocation of intracellular N-terminal truncated isoform of MMP-2 (NT-MMP-2) from mitochondria-associated membrane (MAM) into mitochondria. In the onset of diabetic cardiomyopathy, mitochondrial impairment in cardiomyocytes is characterized by the dysregulation of the different MMP-2 isoforms. This can imply the generation of a “frail” myocardial tissue unable to adapt itself to stress.

show abstract

I(f) current channel inhibitor (ivabradine) deserves cardioprotective effect via down-regulating the expression of matrix metalloproteinase (MMP)-2 and attenuating apoptosis in diabetic mice

Cited by 21 publications

References 37 publications

Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts

Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Role of TSPO/VDAC1 Upregulation and Matrix Metalloproteinase-2 Localization in the Dysfunctional Myocardium of Hyperglycaemic Rats

Contact Info

Product

Resources

About