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Abstract
In the present study, we investigated a novel signaling target in diabetic cardiomyopathy where inflammation induces caspase-1-dependent cell death, pyroptosis, involving Nek7-GBP5 activators to activate the NLRP3 inflammasome, destabilizes cardiac structure and neovascularization. Furthermore, we explored the therapeutic ability of bone morphogenetic protein-7 (BMP-7) to attenuate these adverse effects. C57BL/6J mice (n = 16 mice/group) were divided into: control (200 mg/kg, 0.9% saline intraperitoneal injection, i.p.); Streptozotocin (STZ) and STZ-BMP-7 groups (STZ, 200 mg/kg, i.p. injection). After 6 weeks, heart function was examined with echocardiography, and mice were sacrificed. Immunostaining, Western blotting, H&E, and Masson’s trichrome staining was performed on heart tissues. STZ-induced diabetic cardiomyopathy significantly increased inflammasome formation (TLR4, NLRP3, Nek7, and GBP5), pyroptosis markers (caspase-1, IL-1β, and IL-18), inflammatory cytokines (IL-6 and TNF-α), MMP9, and infiltration of monocytes (CD14), macrophage (iNOS), and dendritic cells (CD11b and CD11c) (p < 0.05). Moreover, a significant endothelial progenitor cells (EPCs) dysfunction (c-Kit/FLk-1, CD31), adverse cardiac remodeling, and reduction in left ventricular (LV) heart function were observed in STZ versus control (p < 0.05). Treatment with BMP-7 significantly reduced inflammasome formation, pyroptosis, and inflammatory cytokines and infiltrated inflammatory cells. In addition, BMP-7 treatment enhanced EPC markers and neovascularization and subsequently improved cardiac remodeling in a diabetic heart. Moreover, a significant improvement in LV heart function was achieved after BMP-7 administration relative to diabetic mice (p < 0.05). In conclusion, BMP-7 attenuated inflammation-induced pyroptosis, adverse cardiac remodeling, and improved heart function via the TLR4-NLRP3 inflammasome complex activated by novel signaling Nek7/GBP5. Our BMP-7 pre-clinical studies of mice could have significant potential as a future therapy for diabetic patients.
Highlights
The prevalence of diabetic cardiomyopathy is found to be ~17% of the diabetic population, with a significant increased risk of heart failure in type-1 and type-2 diabetes [1]
Image quantification showed a significant increase of toll-like receptor-4 (TLR4) (Figure 2C, p < 0.001) and NLRP3 (Figure 2E, p < 0.001) expression levels in cardiac myocytes in the STZ-induced diabetic cardiomyopathy group compared to the control
Treatment with bone morphogenetic protein-7 (BMP-7) attenuates the expression of TLR4 (Figure 2D, p = 0.027) and NLRP3 (Figure 2F, p = 0.033) compared to the STZ-induced diabetic cardiomyopathy. These results indicate the therapeutic effect of BMP-7 in the attenuation of TLR4 and NLRP3 inflammasome formation
Summary
The prevalence of diabetic cardiomyopathy is found to be ~17% of the diabetic population, with a significant increased risk of heart failure in type-1 and type-2 diabetes [1]. Diabetic cardiomyopathy is characterized by an alteration of cardiac structure and left ventricular dysfunction in the absence of other cardiac risk factors such as coronary artery diseases or hypertension [1]. The exact nature of inflammation in the diabetic heart and its involvement in the disease progression remains unknown. Whether the presence of inflammation involves the recently recognized pyroptotic cell death in the diabetic heart [5,6] has gained attraction, but detailed understanding on inflammatory cells and the pyroptotic pathway remains unknown. The prevalence of the pyroptotic pathway as well as addition signaling molecules in diabetic cardiomyopathy is complex and understudied. The cutting-edge research that we present in this paper aims to understand those molecular mechanisms and establishes a potential therapeutic agent to attenuate such a pathway
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