Engulfment and cell motility protein 1 potentiates diabetic cardiomyopathy via Rac-dependent and Rac-independent ROS production

Kakoki, Masao; Bahnson, Edward Moreira; Hagaman, John R.; Siletzky, Robin M.; Grant, Ruriko; Kayashima, Yukako; Li, Feng; Lee, Esther Y; Sun, Michelle; Taylor, Joan M.; Rice, Jessica C; Almeida, Michael F.; Bahr, Ben A.; Jennette, J. Charles; Smithies, Oliver; Maeda-Smithies, Nobuyo

doi:10.1172/jci.insight.127660

Cited by 13 publications

(6 citation statements)

References 69 publications

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“…Mitochondrial oxidative damage and mitochondrial dysfunction contribute to the progression of diabetic cardiomyopathy [25][26][27]; however, the cause of mitochondrial dysfunction and the source of mitochondrial ROS were largely unclear [28] [29,30]. Our study found that Akap1 deficiency caused NDUFS1 retention in the cytosol and blocked its translocation into mitochondria, which resulted in increased mitochondrial ROS production and impaired mitochondrial function.…”

Section: Discussionmentioning

confidence: 62%

Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis

Zhao

et al. 2020

Diabetologia

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Aims/hypothesis Diabetic cardiomyopathy, characterised by increased oxidative damage and mitochondrial dysfunction, contributes to the increased risk of heart failure in individuals with diabetes. Considering that A-kinase anchoring protein 121 (AKAP1) is localised in the mitochondrial outer membrane and plays key roles in the regulation of mitochondrial function, this study aimed to investigate the role of AKAP1 in diabetic cardiomyopathy and explore its underlying mechanisms. Methods Loss-and gain-of-function approaches were used to investigate the role of AKAP1 in diabetic cardiomyopathy. Streptozotocin (STZ) was injected into Akap1-knockout (Akap1-KO) mice and their wild-type (WT) littermates to induce diabetes. In addition, primary neonatal cardiomyocytes treated with high glucose were used as a cell model of diabetes. Cardiac function was assessed with echocardiography. Akap1 overexpression was conducted by injecting adeno-associated virus 9 carrying Akap1 (AAV9-Akap1). LC-MS/MS analysis and functional experiments were used to explore underlying molecular mechanisms. Results AKAP1 was downregulated in the hearts of STZ-induced diabetic mouse models. Akap1-KO significantly aggravated cardiac dysfunction in the STZ-treated diabetic mice when compared with WT diabetic littermates, as evidenced by the left ventricular ejection fraction (LVEF; STZ-treated WT mice [WT/STZ] vs STZ-treated Akap1-KO mice [KO/STZ], 51.6% vs 41.6%). Mechanistically, Akap1 deficiency impaired mitochondrial respiratory function characterised by reduced ATP production. Additionally, Akap1 deficiency increased cardiomyocyte apoptosis via enhanced mitochondrial reactive oxygen species (ROS) production. Furthermore, immunoprecipitation and mass spectrometry analysis indicated that AKAP1 interacted with the NADH-ubiquinone oxidoreductase 75 kDa subunit (NDUFS1). Specifically, Akap1 deficiency inhibited complex I activity by preventing translocation of NDUFS1 from the cytosol to mitochondria. Akap1 deficiency was also related to decreased ATP production and enhanced mitochondrial ROS-related apoptosis. In contrast, restoration of AKAP1 expression in the hearts of STZ-treated diabetic mice promoted translocation of NDUFS1 to mitochondria and alleviated diabetic cardiomyopathy in the Bingchao Qi, Linjie He and Ya Zhao contributed equally to this work.

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Section: Discussionmentioning

confidence: 62%

Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis

Zhao

et al. 2020

Diabetologia

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“…Interestingly, MT1G expression was significantly upregulated in islets from T2D subjects obtained by laser capture microdissection 38 . ELMO1 is required for phagocytosis of apoptotic cells and cell motility, and single nucleotide polymorphisms (SNPs) tagged to ELMO1 are associated with diabetic nephropathy in T1D and T2D 39 , 40 . Upregulation of ELMO1 expression is associated with increased cell stress; thus, its downregulation in AAb islets may represent enhanced cell protection responses.…”

Section: Resultsmentioning

confidence: 99%

Islet sympathetic innervation and islet neuropathology in patients with type 1 diabetes

Campbell-Thompson

Butterworth

Boatwright

et al. 2021

Sci Rep

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Dysregulation of glucagon secretion in type 1 diabetes (T1D) involves hypersecretion during postprandial states, but insufficient secretion during hypoglycemia. The sympathetic nervous system regulates glucagon secretion. To investigate islet sympathetic innervation in T1D, sympathetic tyrosine hydroxylase (TH) axons were analyzed in control non-diabetic organ donors, non-diabetic islet autoantibody-positive individuals (AAb), and age-matched persons with T1D. Islet TH axon numbers and density were significantly decreased in AAb compared to T1D with no significant differences observed in exocrine TH axon volume or lengths between groups. TH axons were in close approximation to islet α-cells in T1D individuals with long-standing diabetes. Islet RNA-sequencing and qRT-PCR analyses identified significant alterations in noradrenalin degradation, α-adrenergic signaling, cardiac β-adrenergic signaling, catecholamine biosynthesis, and additional neuropathology pathways. The close approximation of TH axons at islet α-cells supports a model for sympathetic efferent neurons directly regulating glucagon secretion. Sympathetic islet innervation and intrinsic adrenergic signaling pathways could be novel targets for improving glucagon secretion in T1D.

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“…Since hyperglycemia regulates cardiac Ang II and TGF-β levels, both of which are shown to induce cardiac Nox4 expression [ 107 , 112 , 113 ], it can be inferred that the regulation of Nox4 by Ang II or TGF-β may play a critical role in the pathogenesis of diabetic cardiomyopathy. Reports have unveiled the interaction between Ang II and Nox4 in diabetic myocardial tissues and cells.…”

Section: Nox4 and Diabetic Microangiopathymentioning

confidence: 99%

“…TGF-β is a cardiac cytokine and a potent pro-fibrotic marker involved in the development of cardiac fibrosis and heart failure. Similar to Ang II, upregulation of Nox4 in animal or cellular models of diabetic cardiomyopathy is usually associated with increased TGF-β expression [ 98 , 99 , 101 , 105 , 109 , 112 ]. Ang II and TGF-β play a key role in myocardial hypertrophy and fibrosis, and Ang II-induced TGF-β expression in cardiomyocytes and fibroblasts is prerequisite for Ang II-mediated myocardial hypertrophy and fibrosis [ 114 ].…”

Section: Nox4 and Diabetic Microangiopathymentioning

confidence: 99%

“… [ 110 ] The myocardial tissue of STZ-induced diabetic rat Ang II receptor blockers Ang II/Nox4 AT1R↓, Nox4↓, p22phox↓, Oxidative stress↓, TGF-β↓, improved cardiac function The regulation of Nox4 by Ang II or TGF-β may play a critical role in the pathogenesis of diabetic cardiomyopathy. [ 99 , 107 , 112 , 113 ] The myocardial tissue of diabetic hamsters Chymase-specific inhibitor (TEI-F00806/TEI-E00548) Chymase/Ang II 8-OHdG↓, Nox4↓, Ang II↓, fibrosis indexes↓ Chymase inhibition might prevent oxidative stress and diabetic cardiomyopathy at an early stage by reducing local AngII production. [ 107 ] Diabetic mice – FOXO1 KLF5↑, Nox4↑, ceramide accumulation and cardiac dysfunction KLF5 is a new therapeutic target for the prevention and treatment of diabetic cardiomyopathy.…”

Section: Nox4 and Diabetic Microangiopathymentioning

confidence: 99%

See 1 more Smart Citation

Nox4 as a novel therapeutic target for diabetic vascular complications

Wang¹,

Luo²,

Zhou³

et al. 2023

Redox Biology

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Engulfment and cell motility protein 1 potentiates diabetic cardiomyopathy via Rac-dependent and Rac-independent ROS production

Cited by 13 publications

References 69 publications

Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis

Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis

Islet sympathetic innervation and islet neuropathology in patients with type 1 diabetes

Nox4 as a novel therapeutic target for diabetic vascular complications

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