bims-hafaim 2023-05-07 papers

Issue of 2023–05–07
four papers selected by
Kyle McCommis, Saint Louis University

JACC Basic Transl Sci. 2023 Apr;8(4): 422-435

Western Diet Causes Heart Failure With Reduced Ejection Fraction and Metabolic Shifts After Diastolic Dysfunction and Novel Cardiac Lipid Derangements.

Santosh K Maurya, Andrew N Carley, Chandan K Maurya, E Douglas Lewandowski.

Western diet (WD) impairs glucose tolerance and cardiac lipid dynamics, preceding heart failure with reduced ejection fraction (HFrEF) in mice. Unlike diabetic db/db mice with high cardiac triglyceride (TG) and rapid TG turnover, WD mice had high TG but slowed turnover, reducing lipolytic PPAR⍺ activation. WD deranged cardiac TG dynamics by imbalancing synthesis and lipolysis, with low cardiac TG lipase (ATGL), low ATGL co-activator, and high ATGL inhibitory peptide. By 24 weeks of WD, hearts shifted from diastolic dysfunction to diastolic dysfunction with HFrEF with decreases in GLUT4 and exogenous glucose oxidation and elevated β-hydroxybutyrate dehydrogenase 1 without increasing ketone oxidation.

Keywords: HFpEF; HFrEF; Western diet; metabolism; triglyceride turnover

DOI: https://doi.org/10.1016/j.jacbts.2022.10.009

bioRxiv. 2023 Apr 18. pii: 2023.04.17.537222. [Epub ahead of print]

MCU gain-and loss-of-function models define the duality of mitochondrial calcium uptake in heart failure.

Joanne F Garbincius, Timothy S Luongo, Jonathan P Lambert, Adam S Mangold, Emma K Murray, Alycia N Hildebrand, Pooja Jadiya, John W Elrod.

Background: Mitochondrial calcium ( m Ca 2+ ) uptake through the mitochondrial calcium uniporter channel (mtCU) stimulates metabolism to meet acute increases in cardiac energy demand. However, excessive m Ca 2+ uptake during stress, as in ischemia-reperfusion, initiates permeability transition and cell death. Despite these often-reported acute physiological and pathological effects, a major unresolved controversy is whether mtCU-dependent m Ca 2+ uptake and long-term elevation of cardiomyocyte m Ca 2+ contributes to the heart's adaptation during sustained increases in workload.
Objective: We tested the hypothesis that mtCU-dependent m Ca 2+ uptake contributes to cardiac adaptation and ventricular remodeling during sustained catecholaminergic stress.
Methods: Mice with tamoxifen-inducible, cardiomyocyte-specific gain (αMHC-MCM x flox-stop-MCU; MCU-Tg) or loss (αMHC-MCM x Mcu fl/fl ; Mcu -cKO) of mtCU function received 2-wk catecholamine infusion.
Results: Cardiac contractility increased after 2d of isoproterenol in control, but not Mcu -cKO mice. Contractility declined and cardiac hypertrophy increased after 1-2-wk of isoproterenol in MCU-Tg mice. MCU-Tg cardiomyocytes displayed increased sensitivity to Ca 2+ - and isoproterenol-induced necrosis. However, loss of the mitochondrial permeability transition pore (mPTP) regulator cyclophilin D failed to attenuate contractile dysfunction and hypertrophic remodeling, and increased isoproterenol-induced cardiomyocyte death in MCU-Tg mice.
Conclusions: mtCU m Ca 2+ uptake is required for early contractile responses to adrenergic signaling, even those occurring over several days. Under sustained adrenergic load excessive MCU-dependent m Ca 2+ uptake drives cardiomyocyte dropout, perhaps independent of classical mitochondrial permeability transition pore opening, and compromises contractile function. These findings suggest divergent consequences for acute versus sustained m Ca 2+ loading, and support distinct functional roles for the mPTP in settings of acute m Ca 2+ overload versus persistent m Ca 2+ stress.

DOI: https://doi.org/10.1101/2023.04.17.537222

Curr Opin Clin Nutr Metab Care. 2023 May 04.

The role of glucose in cardiac physiology and pathophysiology.

Nikolaos Mylonas, Konstantinos Drosatos, Sobuj Mia.

PURPOSE OF REVIEW: Heart failure is one the major causes of death worldwide and continues to increase despite therapeutics and pharmacology advances. Fatty acids and glucose are used as ATP-producing fuels in heart to meet its energy demands. However, dysregulation of metabolites' use plays a pivotal role in cardiac diseases. How glucose becomes toxic or drives cardiac dysfunction is incompletely understood. In the present review, we summarize the recent findings on cardiac cellular and molecular events that are driven by glucose during pathologic conditions and potential therapeutic strategies to tackle hyperglycemia-mediated cardiac dysfunction.
RECENT FINDINGS: Several studies have emerged recently, demonstrating that excessive glucose utilization has been correlated with impairment of cellular metabolic homeostasis primarily driven by mitochondrial dysfunction and damage, oxidative stress, and abnormal redox signaling. This disturbance is associated with cardiac remodeling, hypertrophy, and systolic and diastolic dysfunction. Both human and animal heart failure studies, report that glucose is a preferable fuel at the expense of fatty acid oxidation during ischemia and hypertrophy, but the opposite happens in diabetic hearts, which warrants further investigation.
SUMMARY: A better understanding of glucose metabolism and its fate during distinct types of heart disease will contribute to developing novel therapeutic options for the prevention and treatment of heart failure.

DOI: https://doi.org/10.1097/MCO.0000000000000943

Acta Pharm Sin B. 2023 Apr;13(4): 1671-1685

Structural repurposing of SGLT2 inhibitor empagliflozin for strengthening anti-heart failure activity with lower glycosuria.

Yixiang Xu, Chao Zhang, Kai Jiang, Xinchun Yang, Feng Chen, Zhiyang Cheng, Jinlong Zhao, Jiaxing Cheng, Xiaokang Li, Xin Chen, Luoyifan Zhou, Hao Duan, Yunyuan Huang, Yaozu Xiang, Jian Li.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC50 > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

Keywords: Empagliflozin; Heart failure; NHE1 (sodium-hydrogen exchanger 1); SGLT2 inhibitor; Structural repurposing

DOI: https://doi.org/10.1016/j.apsb.2022.08.023