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The MEK inhibitor U0126 ameliorates diabetic cardiomyopathy by restricting XBP1's phosphorylation dependent SUMOylation.

ABSTRACT: Background: Chronic diabetes accelerates vascular dysfunction often resulting in cardiomyopathy but underlying mechanisms remain unclear. Recent studies have shown that the deregulated unfolded protein response (UPR) dependent on highly conserved IRE1α-spliced X-box- binding protein (XBP1s) and the resulting endoplasmic reticulum stress (ER-Stress) plays a crucial role in the occurrence and development of diabetic cardiomyopathy (DCM). In the present study, we determined whether targeting MAPK/ERK pathway using MEK inhibitor U0126 could ameliorate DCM by regulating IRE1α-XBP1s pathway. Method: Three groups of 8-week-old C57/BL6J mice were studied: one group received saline injection as control (n=8) and two groups were made diabetic by streptozotocin (STZ) (n=10 each). 18 weeks after STZ injection and stable hyperglycemia, one group had saline treatment while the second group was treated with U0126 (1mg/kg/day), 8 weeks later, all groups were sacrificed. Cardiac function/histopathological changes were determined by echocardiogram examination, Millar catheter system, hematoxylin-eosin staining and western blot analysis. H9C2 cardiomyocytes were employed for in vitro studies. Results: Echocardiographic, hemodynamic and histological data showed overt myocardial hypertrophy and worsened cardiac function in diabetic mice. Chronic diabetic milieu enhanced SUMOylation and impaired nuclear translocation of XBP1s. Intriguingly, U0126 treatment significantly ameliorated progression of DCM, and this protective effect was achieved through enriching XBP1s' nuclear accumulation. Mechanistically, U0126 inhibited XBP1s' phosphorylation on S348 and SUMOylation on K276 promoting XBP1s' nuclear translocation. Collectively, these results identify that MEK inhibition restores XBP1s-dependent UPR and protects against diabetes-induced cardiac remodeling. Conclusion: The current study identifies previously unknown function of MEK/ERK pathway in regulation of ER-stress in DCM. U0126 could be a therapeutic target for the treatment of DCM.

SUBMITTER: Wang T

PROVIDER: S-EPMC8375222 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Diabetic cardiomyopathy (DCM) is a complication of diabetes that can cause damage to myocardial structure and function. Metformin (Met) is a widely used type 2 diabetes treatment drug that exerts cardioprotective effects through multiple pathways. Prokineticin 2 (PK2) is a small-molecule secreted protein that plays pivotal parts in cardiomyocyte survival and angiogenesis. However, the role of Met in regulating the PK2 signaling pathway in DCM remains unclear. This experiment explored the effects of Met on high glucose (HG)-induced injury through the PK2/PKR pathway in vivo and in vitro. Cardiomyocytes isolated from adult or AKT-knockout mice were treated with HG (33 mmol/L) and PK2 or AKT1/2 kinase inhibitor (AKT inhibitor). Heart contraction properties based on cell shortening were evaluated; these properties included the resting cell length, peak shortening (PS), maximum speed of shortening/relengthening (±dL/dt), time to 90% relengthening (TR90), and time to peak shortening (TPS). Mice with streptozotocin-induced diabetes were treated with Met to evaluate cardiac function, myocardial structure, and the PK2/PKR and AKT/GSK3? pathways. Moreover, H9c2 cardiomyocytes were exposed to HG in the absence or presence of Met with or without the PK2 antagonist PKRA7 or the AKT inhibitor, and apoptotic proteins such as Bax and Bcl-2 and the PK2/PKR and AKT/GSK3? pathways were evaluated using western blot analysis. The prolongation of TR90 and decreases in PS and ±dL/dt caused by HG were ameliorated by PK2 in cardiomyocytes, but the effects of PK2 were ameliorated or negated by the AKT inhibitor and in AKT-knockout mice. Diabetic mice showed metabolic abnormalities, aberrant myocardial enzyme levels, declines in myocardial systolic and diastolic function associated with myocardial fibrosis, and pronounced apoptosis, but these effects were greatly rescued by Met treatment. Moreover, PK2, PKR1, and PKR2 expression and p-AKT/AKT and p-GSK3?/GSK3? ratios were decreased in diabetic mice, and these decreases were attenuated by Met. Likewise, H9c2 cells exposed to HG showed reduced PK2/PKR expression and decreased p-AKT/AKT and p-GSK3?/GSK3? ratios, and these effects were nullified by Met. In addition, the effects of Met on cardiomyocytes exposed to HG were abolished after intervention with PKRA7 or the AKT inhibitor. These results suggest that Met can activate the PK2/PKR-mediated AKT/GSK3? pathway, thus improving cardiac function and alleviating apoptosis in DM mice.

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The MEK inhibitor U0126 ameliorates diabetic cardiomyopathy by restricting XBP1's phosphorylation dependent SUMOylation.

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