Calhex231 Alleviates High Glucose-Induced Myocardial Fibrosis via Inhibiting Itch-Ubiquitin Proteasome Pathway in Vitro

Jun 7, 2019Biological & pharmaceutical bulletin

Calhex231 reduces high sugar–caused heart tissue scarring by blocking a protein breakdown pathway in lab cells

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Abstract

After 12 weeks, type 1 diabetic rats exhibited clear contractile dysfunction and collagen deposition.

High glucose conditions increased the expression of the calcium sensing receptor and factors related to fibrosis in cardiac fibroblasts.
Increased calcium sensing receptor activation was linked to higher intracellular calcium levels and changes in specific protein expressions.
Treatment with the calcium sensing receptor inhibitor Calhex reduced cardiac fibroblast proliferation and collagen deposition.
Calhex may inhibit pathways associated with fibrosis, suggesting its potential as a therapeutic agent for diabetic cardiomyopathy.

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Diabetic cardiomyopathy (DCM) is a major complication of diabetes, and features myocardial fibrosis as its main pathological feature. Calcium sensing receptor (CaSR) is a G protein-coupled receptor, which involves in myocardial fibrosis by regulation of calcium homeostasis. Calhex, the CaSR inhibitor, is not clear whether it regulates myocardial fibrosis in DCM. In the present study, type 1 diabetic (T1D) rats and primary neonatal rat cardiac fibroblasts were used to observe the role of Calhex. In vivo experiments showed that in the T1D group, contractile dysfunction and the deposition of collagen I and III were obvious after 12 weeks. In vitro experiments, we found that high glucose (HG) could increase the expression of CaSR, α-smooth muscle actin (α-SMA), transforming growth factor-β(TGF-β) collagen I/III, matrix metalloproteinase-2 (MMP-2), MMP9, along with cardiac fibroblast migration and proliferation. We further demonstrated that CaSR activation increased intracellular Caconcentration and upregulated the expression of Itch (atrophin-1 interacting protein 4), which resulted in increasing the ubiquitination levels of Smad7 and upregulating the expression of p-Smad2, p-Smad3. However, treatment with Calhexclearly inhibited the above-mentioned changes. Collectively these results suggest that Calhexcould inhibit Itch-ubiquitin proteasome and TGF-β/Smads pathways, and then depress the proliferation of cardiac fibroblasts, along with the reduction deposition of collagen, alleviate glucose-induced myocardial fibrosis. Our findings indicate an important new mechanism for myocardial fibrosis, and suggest Calhexwould be a new therapeutic agent for the treatment of DCM. 231 231 1 1 231 231 1 231 2+

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Calhex231 Alleviates High Glucose-Induced Myocardial Fibrosis via Inhibiting Itch-Ubiquitin Proteasome Pathway in Vitro

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