LCZ696 improves cardiac function via alleviating Drp1-mediated mitochondrial dysfunction in mice with doxorubicin-induced dilated cardiomyopathy

Yan, Xia; Chen, Zhangwei; Chen, Ao; Fu, Mingqiang; Dong, Zhen; Hu, Kai; Yang, Xiangdong; Zou, Yunzeng; Sun, Aijun; Qian, Juying; Ge, Junbo

doi:10.1016/j.yjmcc.2017.06.003

Cited by 116 publications

(110 citation statements)

References 34 publications

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“…Abnormally expressed Drp1 has been observed in various cardiac damages including ischemia-reperfusion injury and dilated cardiomyopathy [28,29]. Besides, accumulated evidences suggested that Drp1-dependent mitochondrial fragmentation is closely associated with its phosphorylation status at different amino acid sites, and the phosphorylation of Ser616 was highly related to mitochondrial fission [29].…”

Section: Oxidative Medicine and Cellular Longevitymentioning

confidence: 99%

Astaxanthin Attenuates Hypertensive Vascular Remodeling by Protecting Vascular Smooth Muscle Cells from Oxidative Stress-Induced Mitochondrial Dysfunction

Chen

Guo

et al. 2020

Oxidative Medicine and Cellular Longevity

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Oxidative stress aggravates mitochondrial injuries and accelerates the proliferation of vascular smooth muscle cells (VSMCs), which are important mechanisms contributing to vascular remodeling in hypertension. We put forward the hypothesis that Astaxanthin (ATX), known to possess strong features of antioxidant, could attenuate vascular remodeling by inhibiting VSMC proliferation and improving mitochondrial function. The potential effects of ATX were tested on spontaneously hypertensive rats (SHRs) and cultured VSMCs that injured by angiotensin II (Ang II). The results showed that ATX lowered blood pressure, reduced aortic wall thickness and fibrosis, and decreased the level of reactive oxygen species (ROS) and H 2 O 2 in tunica media. Moreover, ATX decreased the expression of proliferating cell nuclear antigen (PCNA) and ki67 in aortic VSMCs. In vitro, ATX mitigated VSMC proliferation and migration, decreased the level of cellular ROS, and balanced the activities of ROSrelated enzymes including NADPH oxidase, xanthine oxidase, and superoxide dismutase (SOD). Besides, ATX mitigated Ca 2+ overload, the overproduction of mitochondrial ROS (mtROS), mitochondrial dysfunction, mitochondrial fission, and Drp1 phosphorylation at Ser616. In addition, ATX enhanced mitophagy and mitochondrial biosynthesis by increasing the expression of PINK, parkin, mtDNA, mitochondrial transcription factor A (Tfam), and PGC-1α. The present study indicated that ATX could efficiently treat vascular remodeling through restraining VSMC proliferation and restoring mitochondrial function. Inhibiting mitochondrial fission by decreasing the phosphorylation of Drp1 and stimulating mitochondrial autophagy and biosynthesis via increasing the expression of PINK, parkin, Tfam, and PGC-1α may be part of its underlying mechanisms.

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Section: Oxidative Medicine and Cellular Longevitymentioning

confidence: 99%

Astaxanthin Attenuates Hypertensive Vascular Remodeling by Protecting Vascular Smooth Muscle Cells from Oxidative Stress-Induced Mitochondrial Dysfunction

Chen

Guo

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…; Xia et al. ), and this serine residue is phosphorylated by cyclin‐dependent kinase 1 (CDK1)/cyclin B (Taguchi et al. ), protein kinase C delta (Qi et al.…”

Section: Discussionmentioning

confidence: 99%

“…We do not have a clear explanation for how phospho-Ser616 Drp1 level was increased after MI in OLETF. In the heart, Drp1 phosphorylation at Ser616 is increased by various stresses (Shirakabe et al 2016;Xu et al 2016;Tsushima et al 2017;Xia et al 2017), and this serine residue is phosphorylated by cyclin-dependent kinase 1 (CDK1)/cyclin B (Taguchi et al 2007), protein kinase C delta (Qi et al 2011), extracellular regulated kinase (ERK) (Prieto et al 2016), and Ca 2+ /calmodulin-dependent kinase II (CaMKII) (Xu et al 2016). CaMKII is activated in the noninfarct area after MI (Singh et al 2012), and the level of oxidized CaMKII, an activated form of CaM-KII, has been reported to be increased in the diabetic myocardium (Luo et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts

et al. 2018

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To explore mechanisms by which SGLT2 inhibitors protect diabetic hearts from heart failure, we examined the effect of empagliflozin (Empa) on the ultrastructure of cardiomyocytes in the noninfarcted region of the diabetic heart after myocardial infarction (MI). OLETF, a rat model of type 2 diabetes, and its nondiabetic control, LETO, received a sham operation or left coronary artery ligation 12 h before tissue sampling. Tissues were sampled from the posterior ventricle (i.e., the remote noninfarcted region in rats with MI). The number of mitochondria was larger and small mitochondria were more prevalent in OLETF than in LETO. Fis1 expression level was higher in OLETF than in LETO, while phospho‐Ser637‐Drp1, total Drp1, Mfn1/2, and OPA1 levels were comparable. MI further reduced the size of mitochondria with increased Drp1‐Ser616 phosphorylation in OLETF. The number of autophagic vacuoles was unchanged after MI in LETO but was decreased in OLETF. Lipid droplets in cardiomyocytes and tissue triglycerides were increased in OLETF. Empa administration (10 mg/kg per day) reduced blood glucose and triglycerides and paradoxically increased lipid droplets in cardiomyocytes in OLETF. Empa suppressed Fis1 upregulation, increased Bnip3 expression, and prevented reduction in both mitochondrial size and autophagic vacuole number after MI in OLETF. Together with the results of our parallel study showing upregulation of SOD2 and catalase by Empa, the results indicate that Empa normalizes the size and number of mitochondria in diabetic hearts and that diabetes‐induced excessive reduction in mitochondrial size after MI was prevented by Empa via suppression of ROS and restoration of autophagy.

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“…Other studies on animal models indicate that the modulation of the expression of genes involved in FA metabolism [42][43][44][45], mitochondrial dynamics [46,47] and integrity [48] can induce also DCM features, although it is not clear whether the same mechanisms occur also in human patients.…”

Section: Perturbation Of Mitochondrial Genes Recapitulating Dcmmentioning

confidence: 99%

Metabolic Alterations in Inherited Cardiomyopathies

Sacchetto

Sequeira

Bertero

et al. 2019

JCM

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The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. These genetic diseases are characterized by cardiac structural and functional anomalies in the absence of abnormal conditions that can explain the observed myocardial abnormality, and are frequently associated with heart failure. Since their original description, major advances have been achieved in the genetic and phenotype knowledge, highlighting the involvement of metabolic abnormalities in their pathogenesis. This review provides a brief overview of the role of mitochondria in the energy metabolism in the heart and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.

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LCZ696 improves cardiac function via alleviating Drp1-mediated mitochondrial dysfunction in mice with doxorubicin-induced dilated cardiomyopathy

Cited by 116 publications

References 34 publications

Astaxanthin Attenuates Hypertensive Vascular Remodeling by Protecting Vascular Smooth Muscle Cells from Oxidative Stress-Induced Mitochondrial Dysfunction

Astaxanthin Attenuates Hypertensive Vascular Remodeling by Protecting Vascular Smooth Muscle Cells from Oxidative Stress-Induced Mitochondrial Dysfunction

Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts

Metabolic Alterations in Inherited Cardiomyopathies

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