bims-hafaim 2024-02-04 papers

Issue of 2024–02–04
four papers selected by
Kyle McCommis, Saint Louis University

Circ Res. 2024 Feb 01.

LncRNA CHKB-DT Downregulation Enhances Dilated Cardiomyopathy Through ALDH2.

Xiang Nie, Jiahui Fan, Beibei Dai, Zheng Wen, Huaping Li, Chen Chen, Dao Wen Wang.

BACKGROUND: Human cardiac long noncoding RNA (lncRNA) profiles in patients with dilated cardiomyopathy (DCM) were previously analyzed, and the long noncoding RNA CHKB (choline kinase beta) divergent transcript (CHKB-DT) levels were found to be mostly downregulated in the heart. In this study, the function of CHKB-DT in DCM was determined.
METHODS: Long noncoding RNA expression levels in the human heart tissues were measured via quantitative reverse transcription-polymerase chain reaction and in situ hybridization assays. A CHKB-DT heterozygous or homozygous knockout mouse model was generated using the clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 system, and the adeno-associated virus with a cardiac-specific promoter was used to deliver the RNA in vivo. Sarcomere shortening was performed to assess the primary cardiomyocyte contractility. The Seahorse XF cell mitochondrial stress test was performed to determine the energy metabolism and ATP production. Furthermore, the underlying mechanisms were explored using quantitative proteomics, ribosome profiling, RNA antisense purification assays, mass spectrometry, RNA pull-down, luciferase assay, RNA-fluorescence in situ hybridization, and Western blotting.
RESULTS: CHKB-DT levels were remarkably decreased in patients with DCM and mice with transverse aortic constriction-induced heart failure. Heterozygous knockout of CHKB-DT in cardiomyocytes caused cardiac dilation and dysfunction and reduced the contractility of primary cardiomyocytes. Moreover, CHKB-DT heterozygous knockout impaired mitochondrial function and decreased ATP production as well as cardiac energy metabolism. Mechanistically, ALDH2 (aldehyde dehydrogenase 2) was a direct target of CHKB-DT. CHKB-DT physically interacted with the mRNA of ALDH2 and FUS (RNA-binding protein FUS) through the GGUG motif. CHKB-DT knockdown aggravated ALDH2 mRNA degradation and 4-hydroxy-2-nonenal production, whereas overexpression of CHKB-DT reversed these molecular changes. Furthermore, restoring ALDH2 expression in CHKB-DT+/- mice alleviated cardiac dilation and dysfunction.
CONCLUSIONS: CHKB-DT is significantly downregulated in DCM. CHKB-DT acts as an energy metabolism-associated long noncoding RNA and represents a promising therapeutic target against DCM.

Keywords: RNA, long noncoding; cardiomyopathy, dilated; choline kinase; energy metabolism; heart failure

DOI: https://doi.org/10.1161/CIRCRESAHA.123.323428

Biochim Biophys Acta Mol Basis Dis. 2024 Jan 26. pii: S0925-4439(24)00023-1. [Epub ahead of print] 167038

NAD in pathological cardiac remodeling: Metabolic regulation and beyond.

Ignacio Norambuena-Soto, Yingfeng Deng, Charles Brenner, Sergio Lavandero, Zhao V Wang.

Nicotinamide adenine dinucleotide (NAD) coenzymes are carriers of high energy electrons in metabolism and also play critical roles in numerous signaling pathways. NAD metabolism is decreased in various cardiovascular diseases. Importantly, stimulation of NAD biosynthesis protects against heart disease under different pathological conditions. In this review, we describe pathways for both generation and catabolism of NAD coenzymes and the respective changes of these pathways in the heart under cardiac diseases, including pressure overload, myocardial infarction, cardiometabolic disease, cancer treatment cardiotoxicity, and heart failure. We next provide an update on the strategies and treatments to increase NAD levels, such as supplementation of NAD precursors, in the heart that prevent or reverse cardiomyopathy. We also introduce the approaches to manipulate NAD consumption enzymes to ameliorate cardiac disease. Finally, we discuss the mechanisms associated with improvements in cardiac function by NAD coenzymes, differentiating between mitochondria-dependent effects and those independent of mitochondrial metabolism.

Keywords: Cardiac remodeling; Heart failure; NAD; Nicotinamide riboside

DOI: https://doi.org/10.1016/j.bbadis.2024.167038

J Am Coll Surg. 2024 Jan 30.

Proteomic Analysis and Sex-Specific Changes in Chronically Ischemic Swine Myocardium Treated with Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin.

Dwight D Harris, Sharif A Sabe, Mark Broadwin, Christopher Stone, Akshay Malhotra, Cynthia M Xu, Mohamed Sabra, M Ruhul Abid, Frank W Sellke.

BACKGROUND: Although sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to improve cardiovascular outcomes in general, little is presently known about any sex-specific changes that may result from this therapy. We sought to investigate and quantify potential sex-specific changes seen with the SGLT-2 inhibitor canagliflozin (CAN) in a swine model of chronic myocardial ischemia.
STUDY DESIGN: Eighteen Yorkshire swine underwent left thoracotomy with placement of an ameroid constrictor. Two weeks post-op, swine were assigned to receive either control (F=5, M=5), or CAN 300 mg daily (F=4, M=4). Following five weeks of therapy, swine underwent myocardial functional measurements and myocardial tissue was sent for proteomic analysis.
RESULTS: Functional measurements showed increased cardiac output, stroke volume, ejection fraction, and ischemic myocardial flow at rest in CAN males compared to control males (all p<0.05). The CAN females had no change in cardiac function when compared to control. Proteomic analysis demonstrated six total up-regulated and 97 down-regulated proteins in the CAN female group compared to the female control. Pathway analysis showed decreases in proteins in the tricarboxylic acidic cycle. The CAN male group had 639 up-regulated and 172 down-regulated proteins compared to male control. Pathway analysis showed increases in pathways related to cellular metabolism and decreases in pathways relevant to the development of cardiomyopathy and to oxidative phosphorylation.
CONCLUSIONS: Males treated with CAN had significant improvements in cardiac function that were not observed in females. Moreover, CAN treatment in males was associated with significantly more changes in protein expression than in females. The increased proteomic changes seen in the male CAN group likely contributed to the more robust changes in cardiac function seen in males treated with CAN.

DOI: https://doi.org/10.1097/XCS.0000000000001021

J Am Heart Assoc. 2024 Jan 31. e033553

Hypoxia Attenuates Pressure Overload-Induced Heart Failure.

BACKGROUND: Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)-induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device-mediated mechanical unloading and circulatory support.
METHODS AND RESULTS: We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia-inducible factor)-1α-mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia-mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device-mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts.
CONCLUSIONS: Hypoxia attenuates LVPO-induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia-mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO-induced heart failure and mediate cardiac recovery following mechanical circulatory support.

Keywords: cardiac hypertrophy; cardiac remodeling; hypoxia; left ventricular assist device; pressure overload

DOI: https://doi.org/10.1161/JAHA.123.033553