Mitochondrial dynamics, regulated by mitochondrial fission, fusion, and trafficking, ensure restructuring of this complex reticulum in response to nutrient availability, molecular signals, and cellular stress. 10.1016/j.yjmcc.2012.02.Mitochondria are organized in the cell in the form of a dynamic, interconnected network. Genetic Loss of Insulin Receptors Worsens Cardiac Efficiency in Diabetes. Regulation of Mitochondrial Dynamics in Acute Kidney Injury in Cell Culture and Rodent Models. Autophagy and Mitophagy in Cardiovascular Disease. Mechanism of Action of a Novel Antivasospasm Drug, HA1077. 10.1038/s41463-xĪsano T., Ikegaki I., Satoh S., Suzuki Y., Shibuya M., Takayasu M., et al. Dysregulation of Mitochondrial Dynamics Proteins Are a Targetable Feature of Human Tumors. p-values were adjusted for comparisons of multiple means.Īnderson G. Scale bar = 20 μm (H) Immunoblotting and quantitative assessment of OPA1, Mfn1, Mfn2, Drp1, Fis1 in NMCMs under 48 h periods of HG stimulation and Fasudil treatment (n = 5) (I) levels of Drp1 phosphorylated at serine 616 in NMCMs under 48 h periods of HG stimulation and Fasudil treatment (n = 5) (J) Representative immunoblots and quantification of the levels of Drp1 phosphorylated at serine 616 in vivo (n = 5). Mitochondrial fission was evaluated by the ratio of mitochondrial length and width, which was plotted for thousands of mitochondria from >10 cells. Confocal laser scanning fluorescence microscope imaging of the mitochondrial morphology. The histograms indicate the ratio of green and red fluorescence (n = 5) (B) DCFH-DA staining and quantitative evaluation of ROS in NMCMs with HG treatment and Fasudil (10 μM) treatment for 48 h (n = 5) (C,E) Immunoblotting and quantitative assessment of 4-HNE in NMCMs (n = 5) (D,F) Cytoplasmic Cytc protein levels, mitochondrial Cytc protein levels in NMCMs under 48 h periods of HG stimulation and Fasudil treatment (n = 5) (G) NMCMs were treated with HG (33 mM and 10 nmol/L insulin) and stained using Mitotracker Red and DAPI (n = 3). Fasudil attenuated the cardiac dysfunction in diabetes by decreasing excessive mitochondrial fission via inhibiting Drp1 phosphorylation at serine 616.ĭRP1 ROCK1 diabetic cardiomyopathy fasudil mitochondrial fission type 2 diabetes.Ĭopyright © 2022 Fan, Li, Liu, Xu, Ji, Chen and Li.įasudil abrogated mitochondrial fission and superoxide generation in hyperglycemia-treated cardiomyocytes (A) The MMP was measured using JC-1 staining. The content of Ser616-phosphorylated dynamin-related protein 1 (Drp1) increased while ROCK1 led to apoptosis in HG-treated cardiomyocytes, which could be partly neutralized by ROCK1 inhibition with Fasudil, consistent with the in vivo results. Mechanistically, ROCK1 inhibition abrogated apoptosis, relieved mitochondrial fission, and efficiently attenuated the escalated production of reactive oxygen species in vitro and in vivo. In vitro, ROCK1 was upregulated in HG-induced cardiomyocytes, and ROCK1 inhibition using Fasudil reversed the increased apoptosis, consistent with in vivo results.

The ROCK1 inhibitor, Fasudil, prevented cardiac dysfunction, fibrosis, oxidative stress and myocardial ultrastructural disorders ( p < 0.05) in the diabetic mice. In vivo, we found that type 2 diabetes enhanced the expression and activation of ROCK1 ( p < 0.05). NMCMs (neonatal mouse ventricular cardiac myocytes) in the control group were treated with 5.5 mM glucose, while those in the High Glucose (HG) group were treated with 33 mM glucose and 10 nmol/L insulin. Type II diabetic mice models were established by inducing insulin resistance through a high-fat diet combined with low-dose streptozotocin (STZ) injection. Herein, we aimed to explore the effect of Fasudil (a ROCK1 inhibitor) on the progress of cardiac dysfunction in type 2 DM (T2DM), and to explore the possible mechanisms. ROCK1 (rho-associated coiled-coil containing protein kinase 1) serves as a pathological factor in several diabetic complications. Diabetes mellitus (DM) often involves cardiovascular complications however, treatment regimens are limited.