Abstract
Diabetic cardiomyopathy (DCM) is a condition associated with significant structural changes including cardiac tissue necrosis, localized fibrosis, and cardiomyocyte hypertrophy. This study sought to assess whether and how FBXL10 can attenuate DCM using a rat streptozotocin (STZ)‐induced DCM model system. In the current study, we found that FBXL10 expression was significantly decreased in diabetic rat hearts. FBXL10 protected cells from high glucose (HG)‐induced inflammation, oxidative stress, and apoptosis in vitro. In addition, FBXL10 significantly activated PKC β2 signaling pathway in H9c2 cells and rat model. The cardiomyocyte‐specific overexpression of FBXL10 at 12 weeks after the initial STZ administration attenuated oxidative stress and inflammation, thereby reducing cardiomyocyte death and preserving cardiac function in these animals. Moreover, FBXL10 protected against DCM via activation of the PKC β2 pathway. In conclusion, FBXL has the therapeutic potential for the treatment of DCM.
Highlights
Diabetic cardiomyopathy (DCM) presents with structural and functional deficits in cardiac tissue in individuals with diabetes that are not associated with hypertension or other coronary artery disease.[1,2] DCM is a major risk factor for heart failure in individuals with diabetes, and at the cellular level, this condition is associated with significant cardiomyocyte depletion, alterations in extracellular matrix composition, and abundant tissue fibrosis.[3,4] Based on a previous study, diabetic males and females are at a two-and five-fold increased risk of heart failure, respectively.[5]
When H9c2 cell apoptosis was measured after high glucose (HG) treatment, we found that protein kinase C (PKC) β2 inhibition abolished FBXL10-mediated protection against HG-induced apoptosis (Figure 3E)
Our study is the first report to indicate that overexpression of FBXL10 in the heart protects against diabetes-related cardiac dysfunction, cell death, inflammation and oxidative damage
Summary
Diabetic cardiomyopathy (DCM) presents with structural and functional deficits in cardiac tissue in individuals with diabetes that are not associated with hypertension or other coronary artery disease.[1,2] DCM is a major risk factor for heart failure in individuals with diabetes, and at the cellular level, this condition is associated with significant cardiomyocyte depletion, alterations in extracellular matrix composition, and abundant tissue fibrosis.[3,4] Based on a previous study, diabetic males and females are at a two-and five-fold increased risk of heart failure, respectively.[5]. The protein kinase C (PKC) family consists of many distinct proteins with different functions and tissue distributions.[20,21] In cardiac tissue, PKC α and PKC β2 are the predominant PKC isoforms.[22] Altered PKC expression and function has been linked to many cardiovascular disease-associated issues including heart failure and ischemia, and PKC inhibition has been shown to protect against structural and functional issues.[23] Hyperglycemia has been identified as a potential causative agent of PKC α and PKC β2 overexpression early in the development of DCM, potentially driving the disease-associated pathology of DCM.[24] how PKC β2 contributes precisely to this process at the molecular level remains unknown. The role of PKC β2 signaling pathway in the regulation of the protection of FBXL10 in STZ-induced cardiac damage was investigated
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