Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload

Igaki, Yusuke; Tanno, Masaya; Sato, Tatsuya; Kouzu, Hidemichi; Ogawa, Toshifumi; Osanami, Arata; Yano, Toshiyuki; Kuno, Atsushi; Miki, Takayuki; Nakamura, Takashi; Miura, Tetsuji

doi:10.1016/j.yjmcc.2021.01.002

Cited by 8 publications

(12 citation statements)

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“…Downregulation of BCKDH expression in cardiomyocytes induced profound metabolic changes that mimic OLETF rat hearts. Together with a series of our studies on the roles of AMPD3 in dysregulated cardiac energetics and excessive production of reactive oxygen species in diabetic hearts (Igaki et al, 2021 ; Kouzu et al, 2015 ; Tatekoshi et al, 2018 ), the present findings provide insights into mechanisms contributing to the development of diabetic cardiomyopathy (Figure 6 ).…”

Section: Discussionsupporting

confidence: 63%

“…[Kouzu et al, 2015 ; Tatekoshi et al, 2018 ]) and subsequent reactive oxygen species (ROS) production (ref. [Igaki et al, 2021 ]). The disrupted BCAA metabolism compromises physiological lipid droplet biogenesis and fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 99%

“…AMP deaminase activity was measured as previously described (Igaki et al, 2021 ; Kouzu et al, 2015 ; Tatekoshi et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…To avoid fatty acid‐induced cardiomyocyte apoptosis (Sparagna et al, 2000 ), we adopted the low palmitate concentration, which has been validated in previous studies (Angelini et al, 2022 ; Readnower et al, 2012 ). OCR was measured as previously described (Igaki et al, 2021 ). In preliminary experiments using NRCMs, we confirmed that 40 μM etomoxir completely blocked the palmitate‐stimulated increase in OCR.…”

Section: Methodsmentioning

confidence: 99%

“…We recently reported that upregulated expression of AMP deaminase 3 (AMPD3), a rate‐limiting enzyme in the purine nucleotide cycle, is involved in abnormal cardiac energetics in Otsuka Long‐Evans‐Tokushima fatty (OLETF) rats, models of type 2 diabetes (T2DM) (Igaki et al, 2021 ; Kouzu et al, 2015 ; Tatekoshi et al, 2018 ). The elevated AMPD activity was associated with ATP depletion during acute pressure overload due to excessive degradation of adenine nucleotides (Kouzu et al, 2015 ; Tatekoshi et al, 2018 ), which subsequently facilitated reactive oxygen species production via downstream xanthine oxidoreductase and led to mitochondrial respiratory failure (Igaki et al, 2021 ). Meanwhile, AMPD3 was found to play a central role in coupling fatty acid and BCAA metabolism in skeletal muscle (Hong et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts

Ogawa

Kouzu

Osanami

et al. 2023

Physiological Reports

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Systemic branched‐chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long‐Evans‐Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched‐chain α‐keto acid dehydrogenase (BCKDH), a rate‐limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long‐Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH‐E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3‐E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3‐BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3‐BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.

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Section: Discussionsupporting

confidence: 63%