bims-hafaim 2022-02-13 papers

Issue of 2022–02–13
five papers selected by
Kyle McCommis, Saint Louis University

Cardiovasc Drugs Ther. 2022 Feb 12.

Branched-Chain Amino Acid Metabolism in the Failing Heart.

Branched-chain amino acids (BCAAs) are essential amino acids which have critical roles in protein synthesis and energy metabolism in the body. In the heart, there is a strong correlation between impaired BCAA oxidation and contractile dysfunction in heart failure. Plasma and myocardial levels of BCAA and their metabolites, namely branched-chain keto acids (BCKAs), are also linked to cardiac insulin resistance and worsening adverse remodelling in the failing heart. This review discusses the regulation of BCAA metabolism in the heart and the impact of depressed cardiac BCAA oxidation on cardiac energy metabolism, function, and structure in heart failure. While impaired BCAA oxidation in the failing heart causes the accumulation of BCAA and BCKA in the myocardium, recent evidence suggested that the BCAAs and BCKAs have divergent effects on the insulin signalling pathway and the mammalian target of the rapamycin (mTOR) signalling pathway. Dietary and pharmacological interventions that enhance cardiac BCAA oxidation and limit the accumulation of cardiac BCAAs and BCKAs have been shown to have cardioprotective effects in the setting of ischemic heart disease and heart failure. Thus, targeting cardiac BCAA oxidation may be a promising therapeutic approach for heart failure.

Keywords: Branched-chain amino acids; Branched-chain keto acids; Cardiac insulin resistance; Glucose oxidation; Heart failure

DOI: https://doi.org/10.1007/s10557-022-07320-4

Curr Heart Fail Rep. 2022 Feb 11.

Mitochondria as Therapeutic Targets in Heart Failure.

Julia Schwemmlein, Christoph Maack, Edoardo Bertero.

PURPOSE OF REVIEW: We review therapeutic approaches aimed at restoring function of the failing heart by targeting mitochondrial reactive oxygen species (ROS), ion handling, and substrate utilization for adenosine triphosphate (ATP) production.
RECENT FINDINGS: Mitochondria-targeted therapies have been tested in animal models of and humans with heart failure (HF). Cardiac benefits of sodium/glucose cotransporter 2 inhibitors might be partly explained by their effects on ion handling and metabolism of cardiac myocytes. The large energy requirements of the heart are met by oxidative phosphorylation in mitochondria, which is tightly regulated by the turnover of ATP that fuels cardiac contraction and relaxation. In heart failure (HF), this mechano-energetic coupling is disrupted, leading to bioenergetic mismatch and production of ROS that drive the progression of cardiac dysfunction. Furthermore, HF is accompanied by changes in substrate uptake and oxidation that are considered detrimental for mitochondrial oxidative metabolism and negatively affect cardiac efficiency. Mitochondria lie at the crossroads of metabolic and energetic dysfunction in HF and represent ideal therapeutic targets.

Keywords: Cardiac metabolism; Elamipretide; Heart failure; MitoQ; Mitochondria; Reactive oxygen species; SGLT2 inhibitors

DOI: https://doi.org/10.1007/s11897-022-00539-0

J Clin Invest. 2022 Feb 08. pii: e150595. [Epub ahead of print]

YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload.

Toshihide Kashihara, Risa Mukai, Shin-Ichi Oka, Peiyong Zhai, Yasuki Nakada, Zhi Yang, Wataru Mizushima, Tsutomu Nakahara, Junco S Warren, Maha Abdellatif, Junichi Sadoshima.

The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is activated and mediates compensatory cardiac hypertrophy in response to acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn caused accumulation of intermediates and metabolites of the glycolytic, auxiliary, and anaplerotic pathways during acute PO. Cardiac hypertrophy was inhibited and heart failure was exacerbated in mice with YAP haploinsufficiency in the presence of acute PO. However, normalization of GLUT1 rescued the detrimental phenotype. PO induced accumulation of glycolytic metabolites, including L-serine, L-aspartate, and malate, in a YAP-dependent manner, thereby promoting cardiac hypertrophy. YAP upregulated the GLUT1 gene through interaction with TEAD1 and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy through activation of the Warburg effect.

Keywords: Cardiology; Cardiovascular disease

DOI: https://doi.org/10.1172/JCI150595

Oxid Med Cell Longev. 2022 ;2022 5067544

Peroxiredoxin-5 Knockdown Accelerates Pressure Overload-Induced Cardiac Hypertrophy in Mice.

Chengyun Hu, Feibiao Dai, Jiawu Wang, Lai Jiang, Di Wang, Jie Gao, Jun Huang, Jianfeng Luo, Fei Tang, Zhetao Zhang, Chaoliang Tang.

A recent study showed that peroxiredoxins (Prxs) play an important role in the development of pathological cardiac hypertrophy. However, the involvement of Prx5 in cardiac hypertrophy remains unclear. Therefore, this study is aimed at investigating the role and mechanisms of Prx5 in pathological cardiac hypertrophy and dysfunction. Transverse aortic constriction (TAC) surgery was performed to establish a pressure overload-induced cardiac hypertrophy model. In this study, we found that Prx5 expression was upregulated in hypertrophic hearts and cardiomyocytes. In addition, Prx5 knockdown accelerated pressure overload-induced cardiac hypertrophy and dysfunction in mice by activating oxidative stress and cardiomyocyte apoptosis. Importantly, heart deterioration caused by Prx5 knockdown was related to mitogen-activated protein kinase (MAPK) pathway activation. These findings suggest that Prx5 could be a novel target for treating cardiac hypertrophy and heart failure.

DOI: https://doi.org/10.1155/2022/5067544

Curr Res Physiol. 2022 ;5 55-62

Diet-induced obese mice are resistant to improvements in cardiac function resulting from short-term adropin treatment.

Dharendra Thapa, Bingxian Xie, Bellina A S Mushala, Manling Zhang, Janet R Manning, Paramesha Bugga, Michael W Stoner, Michael J Jurczak, Iain Scott.

Previous studies have shown that treatment with recombinant adropin, a circulating peptide secreted by the liver and brain, restores glucose utilization in the hearts of diet-induced obese mice. This restoration of fuel substrate flexibility, which is lost in obese and diabetic animals, has the potential to improve contractile function in the diabetic heart. Using an ex vivo approach, we examined whether short-term adropin treatment could enhance cardiac function in a mouse model of diet-induced obesity. Our study showed that acute adropin treatment reduces inhibitory phosphorylation of pyruvate dehydrogenase in primary neonatal cardiomyocytes, and leads to moderate improvements in ex vivo cardiac function in mice fed a low fat diet. Conversely, short-term exposure to adropin led to a small decrease in cardiac function in mice fed a long-term high fat diet. Insulin treatment did not significantly alter cardiac function in adropin treated hearts from either low or high fat diet mice, however acute adropin treatment did moderately restore some aspects of downstream insulin signaling in high fat diet fed mice. Overall, these data suggest that in an ex vivo setting, acute adropin treatment alone is not sufficient to promote improved cardiac function in obese animals.

Keywords: Adropin; Cardiac function; Contractility; High fat diet; Insulin; Mice

DOI: https://doi.org/10.1016/j.crphys.2022.01.005