bims-hafaim 2022-10-30 papers

Issue of 2022‒10‒30
four papers selected by
Kyle McCommis
Saint Louis University

Front Cardiovasc Med. 2022 ;9 999254

Multi-omics insights into potential mechanism of SGLT2 inhibitors cardiovascular benefit in diabetic cardiomyopathy.

Yangbo Xi, Dongping Chen, Zhihui Dong, Jinhua Zhang, Hingcheung Lam, Jiading He, Keyi Du, Can Chen, Jun Guo, Jianmin Xiao.

Background: Metabolic and energy disorders are considered central to the etiology of diabetic cardiomyopathy (DCM). Sodium-glucose cotransporter-2 inhibitors (SGLT2i) can effectively reduce the risk of cardiovascular death and heart failure in patients with DCM. However, the underlying mechanism has not been elucidated.Methods: We established a DCM rat model followed by treatment with empagliflozin (EMPA) for 12 weeks. Echocardiography, blood tests, histopathology, and transmission electron microscopy (TEM) were used to evaluate the phenotypic characteristics of the rats. The proteomics and metabolomics of the myocardium in the rat model were performed to identify the potential targets and signaling pathways associated with the cardiovascular benefit of SGLT2i.
Results: The diabetic rat showed pronounced DCM characterized by mitochondrial pleomorphic, impaired lipid metabolism, myocardial fibrosis, and associated diastolic and systolic functional impairments in the heart. To some extent, these changes were ameliorated after treatment with EMPA. A total of 43 proteins and 34 metabolites were identified as targets in the myocardium of diabetic rats treated with EMPA. The KEGG analysis showed that arachidonic acid is associated with the maximum number of related pathways and may be a potential target of EMPA treatment. Fatty acid (FA) metabolism was enhanced in diabetic hearts, and the perturbation of biosynthesis of unsaturated FAs and arachidonic acid metabolism was a potential enabler for the cardiovascular benefit of EMPA.
Conclusion: SGLT2i ameliorated lipid accumulation and mitochondrial damage in the myocardium of diabetic rats. The metabolomic and proteomic data revealed the potential targets and signaling pathways associated with the cardiovascular benefit of SGLT2i, which provides a valuable resource for the mechanism of SGLT2i.

Keywords: SGLT2 inhibitors; diabetic cardiomyopathy; mechanisms; metabolomics; proteomics

DOI: https://doi.org/10.3389/fcvm.2022.999254

PLoS One. 2022 ;17(10): e0276285

First comprehensive identification of cardiac proteins with putative increased O-GlcNAc levels during pressure overload hypertrophy.

Wei Zhong Zhu, Teresa Palazzo, Mowei Zhou, Dolena Ledee, Heather M Olson, Ljiljana Paša-Tolić, Aaron K Olson.

Protein posttranslational modifications (PTMs) by O-GlcNAc globally rise during pressure-overload hypertrophy (POH). However, a major knowledge gap exists on the specific proteins undergoing changes in O-GlcNAc levels during POH primarily because this PTM is low abundance and easily lost during standard mass spectrometry (MS) conditions used for protein identification. Methodologies have emerged to enrich samples for O-GlcNAcylated proteins prior to MS analysis. Accordingly, our goal was to identify the specific proteins undergoing changes in O-GlcNAc levels during POH. We used C57/Bl6 mice subjected to Sham or transverse aortic constriction (TAC) to create POH. From the hearts, we labelled the O-GlcNAc moiety with tetramethylrhodamine azide (TAMRA) before sample enrichment by TAMRA immunoprecipitation (IP). We used LC-MS/MS to identify and quantify the captured putative O-GlcNAcylated proteins. We identified a total of 700 putative O-GlcNAcylated proteins in Sham and POH. Two hundred thirty-three of these proteins had significantly increased enrichment in POH over Sham suggesting higher O-GlcNAc levels whereas no proteins were significantly decreased by POH. We examined two MS identified metabolic enzymes, CPT1B and the PDH complex, to validate by immunoprecipitation. We corroborated increased O-GlcNAc levels during POH for CPT1B and the PDH complex. Enzyme activity assays suggests higher O-GlcNAcylation increases CPT1 activity and decreases PDH activity during POH. In summary, we generated the first comprehensive list of proteins with putative changes in O-GlcNAc levels during POH. Our results demonstrate the large number of potential proteins and cellular processes affected by O-GlcNAc and serve as a guide for testing specific O-GlcNAc-regulated mechanisms during POH.

DOI: https://doi.org/10.1371/journal.pone.0276285

Circ Res. 2022 Oct 24.

SIRT6 Mitigates Heart Failure With Preserved Ejection Fraction in Diabetes.

Xiaoqian Wu, Huan Liu, Alan Brooks, Suowen Xu, Jinque Luo, Rebbeca Steiner, Deanne M Mickelsen, Christine S Moravec, Alexis D Jeffrey, Eric M Small, Zheng Gen Jin.

RATIONALE: Heart failure with preserved ejection (HFpEF) is a growing health problem without effective therapies. Epidemiological studies indicate that diabetes is a strong risk factor for HFpEF, and about 45% of patients with HFpEF are suffering from diabetes. However, the molecular mechanisms for the association of diabetes and HFpEF are poorly understood.OBJECTIVE: This study was designed to explore whether the longevity gene SIRT6 (sirtuin 6) could regulate endothelial fatty acid (FA) transport and ameliorate HFpEF in diabetes.
METHODS AND RESULTS: We first observed that endothelial SIRT6 expression was markedly diminished in cardiac tissues from heart failure patients with diabetes and diabetic mice with the myriad symptoms of HFpEF, which was induced by the combination of the long-term high-fat diet and one low-dose streptozocin challenge. We then generated a unique humanized SIRT6 transgenic mouse model, in which a single copy of human SIRT6 transgene was engineered at mouse Rosa26 locus and conditionally induced with the Cre-loxP technology. We found that genetically restoring endothelial SIRT6 expression in the diabetic mice ameliorated diastolic dysfunction concurrently with decreased cardiac lipid accumulation. SIRT6 gain- or loss-of-function studies showed that SIRT6 negatively regulated endothelial FA uptake. Mechanistically, SIRT6 suppressed endothelial expression of PPARγ through SIRT6-dependent deacetylation of H3K9 around PPARγ promoter region; and PPARγ downregulation mediated SIRT6-dependent inhibition of endothelial FA uptake. Importantly, oral administration of small molecule SIRT6 activator MDL-800 to diabetic mice mitigated cardiac lipid accumulation and diastolic dysfunction.
CONCLUSIONS: The impairment of endothelial SIRT6 expression links diabetes to HFpEF through altering FA transport across the endothelial barrier. The genetic and pharmacological strategies that restore endothelial SIRT6 function in diabetes alleviated experimental HFpEF by limiting FA overtake and improving cardiac metabolism, thus warranting further clinical evaluation.

Keywords: HFpEF; PPARγ; diabetes; endothelial cells; fatty acid transport

DOI: https://doi.org/10.1161/CIRCRESAHA.121.318988

Theranostics. 2022 ;12(16): 7009-7031

Yap1 modulates cardiomyocyte hypertrophy via impaired mitochondrial biogenesis in response to chronic mechanical stress overload.

Peng Yue, Yue Zhang, Lei Liu, Kaiyu Zhou, Shutao Xia, Mou Peng, Hualin Yan, Xiaoqiang Tang, Zhan Chen, Donghui Zhang, Junling Guo, William T Pu, Yuxuan Guo, Yimin Hua, Yifei Li.

Rationale: Chronic pressure overload is a major trigger of cardiac pathological hypertrophy that eventually leads to heart disease and heart failure. Understanding the mechanisms governing hypertrophy is the key to develop therapeutic strategies for heart diseases. Methods: We built chronic pressure overload mice model by abdominal aortic constriction (AAC) to explore the features of Yes-associated protein 1 (YAP1). Then AAV-cTNT-Cre was applied to Yap1F/F mice to induce mosaic depletion of YAP1. Myh6CreERT2; H11CAG-LSL-YAP1 mice were involved to establish YAP1 overexpression model by Tomaxifen injection. ATAC-seq and bioChIP-seq were used to explore the potential targets of YAP1, which were verified by a series of luciferase reporter assays. Dnm1l and Mfn1 were re-expressed in AAC mice by AAV-cTNT-Dnm1l and AAV-cTNT-Mfn1. Finally, Verteprofin was used to inhibit YAP1 to rescue cardiac hypertrophy. Results: We found that pathological hypertrophy was accompanied with the activation of YAP1. Cardiomyocyte-specific deletion of Yap1 attenuated AAC-induced hypertrophy. Overexpression of YAP1 was sufficient to phenocopy AAC-induced hypertrophy. YAP1 activation resulted in the perturbation of mitochondria ultrastructure and function, which was associated with the repression of mitochondria dynamics regulators Dnm1l and Mfn1. Mitochondrial-related genes Dnm1l and Mfn1, are significantly targeted by TEAD1/YAP complex. Overexpression of Dnm1l and Mfn1 synergistically rescued YAP1-induced mitochondrial damages and cardiac hypertrophy. Pharmacological repression of YAP1 by verteporfin attenuated mitochondrial damages and pathological hypertrophy in AAC-treated mice. Interestingly, YAP1-induced mitochondria damages also led to increased reactive oxidative species, DNA damages, and the suppression of cardiomyocyte proliferation. Conclusion: Together, these data uncovered YAP signaling as a therapeutic target for pressure overload-induced heart diseases and cautioned the efforts to induce cardiomyocyte regeneration by activating YAP.

Keywords: Verteporfin; YAP signaling; mitochondria; pathological hypertrophy

DOI: https://doi.org/10.7150/thno.74563