bims-hafaim 2024-04-28 papers

Issue of 2024‒04‒28
five papers selected by
Kyle McCommis, Saint Louis University

J Mol Cell Cardiol. 2024 Apr 21. pii: S0022-2828(24)00055-5. [Epub ahead of print]191 12-22

AICAR confers prophylactic cardioprotection in doxorubicin-induced heart failure in rats.

Anurag Choksey, Ryan D Carter, Benjamin D Thackray, Vicky Ball, Brett W C Kennedy, Lea Hong Tuan Ha, Eshita Sharma, John Broxholme, Marcos Castro-Guarda, Michael P Murphy, Lisa C Heather, Damian J Tyler, Kerstin N Timm.

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to heart failure (HF). Impaired mitochondrial function is thought to be key factor driving progression into HF. We have previously shown in a rat model of DOX-HF that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and energy metabolism, including fatty acid oxidation. We hypothesised that AMPK activation could restore mitochondrial function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this chronic intravenous rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number, and in the absence of observable AMPK-activation. In addition, we found that AICAR prevented loss of myocardial mass. RNAseq analysis showed that this may be driven by normalisation of pathways associated with ribosome function and protein synthesis, which are impaired in DOX-treated rat hearts. AICAR furthermore prevented dyslipidemia and excessive body-weight loss in DOX-treated rats, which may contribute to preservation of myocardial mass. Though it is unclear whether AICAR exerted its cardioprotective effect through cardiac or extra-cardiac AMPK-activation or via an AMPK-independent effect, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.

Keywords: AICAR; Cardio-oncology; Cardioprotection; Cardiotoxicity; Doxorubicin; Heart failure

DOI: https://doi.org/10.1016/j.yjmcc.2024.04.011

Cardiovasc Diabetol. 2024 Apr 26. 23(1): 144

Sex-specific differences in myocardial glucose metabolic rate in non-diabetic, pre-diabetic and type 2 diabetic subjects.

Elena Succurro, Patrizia Vizza, Francesco Cicone, Velia Cassano, Mattia Massimino, Federica Giofrè, Teresa Vanessa Fiorentino, Maria Perticone, Angela Sciacqua, Pietro Hiram Guzzi, Pierangelo Veltri, Francesco Andreozzi, Giuseppe Lucio Cascini, Giorgio Sesti.

BACKGROUND: Evidence has shown that women with type 2 diabetes (T2DM) have a higher excess risk for cardiovascular disease (CVD) than men with T2DM. Subjects with either T2DM or prediabetes exhibit myocardial insulin resistance, but it is still unsettled whether sex-related differences in myocardial insulin resistance occur in diabetic and prediabetic subjects.METHODS: We aimed to evaluate sex-related differences in myocardial glucose metabolic rate (MRGlu), assessed using dynamic PET with 18F-FDG combined with euglycemic-hyperinsulinemic clamp, in subjects with normal glucose tolerance (NGT; n = 20), prediabetes (n = 11), and T2DM (n = 26).
RESULTS: Women with prediabetes or T2DM exhibited greater relative differences in myocardial MRGlu than men with prediabetes or T2DM when compared with their NGT counterparts. As compared with women with NGT, those with prediabetes exhibited an age-adjusted 35% lower myocardial MRGlu value (P = 0.04) and women with T2DM a 74% lower value (P = 0.006), respectively. Conversely, as compared with men with NGT, men with T2DM exhibited a 40% lower myocardial MRGlu value (P = 0.004), while no significant difference was observed between men with NGT and prediabetes. The statistical test for interaction between sex and glucose tolerance on myocardial MRGlu (P < 0.0001) was significant suggesting a sex-specific association.
CONCLUSIONS: Our data suggest that deterioration of glucose homeostasis in women is associated with a greater impairment in myocardial glucose metabolism as compared with men. The sex-specific myocardial insulin resistance could be an important factor responsible for the greater effect of T2DM on the excess risk of cardiovascular disease in women than in men.

Keywords: Cardiac 18F-FDG PET; Cardiovascular disease; Myocardial glucose metabolism; Prediabetes; Sex-differences; Type 2 diabetes

DOI: https://doi.org/10.1186/s12933-024-02246-7

J Transl Med. 2024 Apr 26. 22(1): 390

CAV3 alleviates diabetic cardiomyopathy via inhibiting NDUFA10-mediated mitochondrial dysfunction.

Ping Guo, Shuiqing Hu, Xiaohui Liu, Miaomiao He, Jie Li, Tingqiong Ma, Man Huang, Qin Fang, Yan Wang.

BACKGROUND: The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated.METHODS: Cardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and functional experiments.
RESULTS: Our findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10.
CONCLUSIONS: The current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.

Keywords: Apoptosis; CAV3; Diabetic cardiomyopathy; Mitochondrial dysfunction; NDUFA10

DOI: https://doi.org/10.1186/s12967-024-05223-6

Nat Cardiovasc Res. 2023 ;2(2): 174-191

KDM8 epigenetically controls cardiac metabolism to prevent initiation of dilated cardiomyopathy.

Abdalla Ahmed, Jibran Nehal Syed, Lijun Chi, Yaxu Wang, Carmina Perez-Romero, Dorothy Lee, Etri Kocaqi, Amalia Caballero, Jielin Yang, Quetzalcoatl Escalante-Covarrubias, Akihiko Ishimura, Takeshi Suzuki, Lorena Aguilar-Arnal, Gerard Bryan Gonzales, Kyoung-Han Kim, Paul Delgado-Olguín.

Cardiac metabolism is deranged in heart failure, but underlying mechanisms remain unclear. Here, we show that lysine demethylase 8 (Kdm8) maintains an active mitochondrial gene network by repressing Tbx15, thus preventing dilated cardiomyopathy leading to lethal heart failure. Deletion of Kdm8 in mouse cardiomyocytes increased H3K36me2 with activation of Tbx15 and repression of target genes in the NAD+ pathway before dilated cardiomyopathy initiated. NAD+ supplementation prevented dilated cardiomyopathy in Kdm8 mutant mice, and TBX15 overexpression blunted NAD+-activated cardiomyocyte respiration. Furthermore, KDM8 was downregulated in human hearts affected by dilated cardiomyopathy, and higher TBX15 expression defines a subgroup of affected hearts with the strongest downregulation of genes encoding mitochondrial proteins. Thus, KDM8 represses TBX15 to maintain cardiac metabolism. Our results suggest that epigenetic dysregulation of metabolic gene networks initiates myocardium deterioration toward heart failure and could underlie heterogeneity of dilated cardiomyopathy.

Keywords: Gene expression analysis; Heart failure; Histone post-translational modifications; Metabolism

DOI: https://doi.org/10.1038/s44161-023-00214-0

Biomedicines. 2024 Apr 18. pii: 894. [Epub ahead of print]12(4):

The Role of Gut Microbiota and Its Metabolites in Patients with Heart Failure.

Krzysztof Cienkowski, Alicja Cienkowska, Karolina Kupczynska, Agata Bielecka-Dabrowa.

Heart failure (HF) is a significant health concern; early detection and prevention are crucial. Recent studies suggest that the gut microbiota and its metabolites may influence HF development and risk factors. We explored this relationship by examining changes in gut microbiota composition and metabolite levels in HF patients. HF patients often exhibit decreased alpha and beta diversity compared to controls, suggesting lower bacterial richness and community variation. Changes in specific bacterial phyla were observed, with decreases in Firmicutes (e.g., Ruminococcus) and Bacteroidetes (e.g., Prevotella) and increases in Proteobacteria (e.g., Escherichia, Shigella, and Klebsiella) and Actinobacteria. Gut-microbiota-related metabolites have been identified, potentially affecting various body systems, including the cardiovascular system. Among these are short-chain fatty acids (SCFAs), betaine, trimethylamine N-oxide (TMAO), phenylalanine, tryptophan-kynurenine, and phenylacetylgutamine (PAGIn). Although SCFAs positively affect our organisms, patients with HF have been observed to experience a decline in bacteria responsible for producing these chemical compounds. There have been indications of possible links between betaine, TMAO, phenylalanine, tryptophan-kynurenine, PAGIn, and heart failure. TMAO and phenylalanine, in particular, show promise as potential prognostic factors. However, their clinical significance has not yet been thoroughly evaluated and requires further investigation.

Keywords: betaine; gut microbiota; heart failure; inflammatory markers; metabolites; phenylalanine; short-chain fatty acids (SCFAs); trimethylamine N-oxide (TMAO)

DOI: https://doi.org/10.3390/biomedicines12040894