bims-hafaim 2023-12-17 papers

Issue of 2023–12–17
four papers selected by
Kyle McCommis, Saint Louis University

Clin Sci (Lond). 2023 Dec 07. pii: CS20231039. [Epub ahead of print]

Regulation of Na+-K+-ATPase Leads to Disturbances of Isoproterenol-induced Cardiac Dysfunction via Interference of Ca2+ -dependent Cardiac Metabolism.

Xiaofei Yan, Meihe Li, Ping Lan, Meng Xun, Ying Zhang, Jinghui Shi, Ruijia Wang, Jin Zheng.

Reductions in Na+-K+-ATPase (NKA) activity and expression are often observed in the progress of various reason-induced heart failure (HF). However, NKA α1 mutation or knockdown cannot cause spontaneous heart disease. Whether the abnormal NKAα1 directly contributes to HF pathogenesis remains unknown. Here, we challenge NKA α1 +/- mice with isoproterenol to evaluate the role of NKA α1 haploinsufficiency in isoproterenol (ISO)-induced cardiac dysfunction. Genetic knockdown of NKAα1 accelerated ISO-induced cardiac cell hypertrophy, heart fibrosis, and dysfunction. Further studies revealed decreased Krebs cycle, fatty acid oxidation, and mitochondrial OXPHOS in the hearts of NKA α1 +/- mice challenged with ISO. In ISO-treated conditions, inhibition of NKA elevated cytosolic Na+, further reduced mitochondrial Ca2+ via mNCE, and then finally downregulated cardiac cell energy metabolism. In addition, a supplement of DRm217 alleviated ISO-induced heart dysfunction, mitigated cardiac remodeling, and improved cytosolic Na+ and Ca2+ elevation and mitochondrial Ca2+ depression in the NKAα1+/- mouse model. The findings suggest that targeting NKA and mitochondria Ca2+ could be a promising strategy in the treatment of heart disease.

Keywords: DRm217; Isoproterenol; Na+-K+-ATPase; cardiac energy metabolism; heart remodeling

DOI: https://doi.org/10.1042/CS20231039

Circulation. 2023 Dec 12. 148(24): 1976-1978

Energetic Basis of Recovered Ejection Fraction in Human Heart Failure.

Joseph R Goldenberg, Allison G Hays, Refaat E Gabr, Michael Schӓr, T Jake Samuel, Lisa R Yanek, Gary Gerstenblith, Paul A Bottomley, Robert G Weiss.

Keywords: adenosine triphosphate; cardiac failure; energy metabolism; magnetic resonance spectroscopy; phosphocreatine

DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.065217

Front Nutr. 2023 ;10 1279066

Branched chain amino acids metabolism in heart failure.

Chenshan Gao, Lei Hou.

As a terminal stage of various cardiovascular diseases, heart failure is of great concern due to its high mortality rate and limited treatment options. Researchers are currently focusing their efforts on investigating the metabolism of carbohydrates, fatty acids, and amino acids to enhance the prognosis of cardiovascular diseases. Simultaneously, branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, play significant roles in blood glucose regulation, protein synthesis, and insulin sensitivity. However, disrupted BCAAs metabolism has been associated with conditions such as hypertension, obesity, and atherosclerosis. This article explores intricate metabolic pathways, unveiling the connection between disrupted BCAAs metabolism and the progression of heart failure. Furthermore, the article discusses therapeutic strategies, assesses the impact of BCAAs on cardiac dysfunction, and examines the potential of modulating BCAAs metabolism as a treatment for heart failure. BCAAs and their metabolites are also considered as biomarkers for evaluating cardiac metabolic risk. In conclusion, this article elucidates the multifaceted roles of BCAAs in heart failure and cardiovascular health, providing guidance for future research and intervention measures.

Keywords: HFpEF – heart failure with preserved ejection fraction; HFrEF – heart failure with reduced ejection fraction; branched-chain amino acids; heart failure; metabolic dysregulation

DOI: https://doi.org/10.3389/fnut.2023.1279066

Mil Med Res. 2023 Dec 11. 10(1): 63

Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid β-oxidation to alleviate diabetic cardiomyopathy.

Meng-Yuan Jiang, Wan-Rong Man, Xue-Bin Zhang, Xiao-Hua Zhang, Yu Duan, Jie Lin, Yan Zhang, Yang Cao, De-Xi Wu, Xiao-Fei Shu, Lei Xin, Hao Wang, Xiao Zhang, Cong-Ye Li, Xiao-Ming Gu, Xuan Zhang, Dong-Dong Sun.

BACKGROUND: Diabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid β-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism.
METHODS: A high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC-MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator.
RESULTS: The expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P < 0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P < 0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P < 0.05). LC-MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P < 0.05). Interestingly, in the presence of Irak2 knockdown, Adipsin overexpression did not further alleviate myocardial mitochondrial destruction and cardiac dysfunction, suggesting a downstream role of Irak2 in Adipsin-induced responses (P < 0.05). Consistent with these findings, overexpression of Adipsin after Irak2 knockdown did not further reduce the accumulation of lipids and their metabolites in the cardiac myocardium, nor did it enhance the oxidation capacity of cardiomyocytes expose to palmitate (PA) (P < 0.05). These results indicated that Irak2 may be a downstream regulator of Adipsin.
CONCLUSIONS: Adipsin improves fatty acid β-oxidation and alleviates mitochondrial injury in DCM. The mechanism is related to Irak2 interaction and inhibition of Irak2 mitochondrial translocation.

Keywords: Diabetic cardiomyopathy; Fatty acid β-oxidation; Mitochondrial function; Mitochondrial translocation

DOI: https://doi.org/10.1186/s40779-023-00493-5