bims-hafaim 2022-06-26 papers

Issue of 2022–06–26
five papers selected by
Kyle McCommis, Saint Louis University

J Am Heart Assoc. 2022 Jun 22. e025021

Postnatal Deletion of Bmal1 in Cardiomyocyte Promotes Pressure Overload Induced Cardiac Remodeling in Mice.

Qing Liang, Hu Xu, Min Liu, Lei Qian, Jin Yan, Guangrui Yang, Lihong Chen.

Background Mice with cardiomyocyte-specific deletion of Bmal1, a core clock gene, had spontaneous abnormal cardiac metabolism, dilated cardiomyopathy, and shortened lifespan. However, the role of cardiomyocyte Bmal1 in pressure overload induced cardiac remodeling is unknown. Here we aimed to understand the contribution of cardiomyocyte Bmal1 to cardiac remodeling in response to pressure overload induced by transverse aortic constriction or chronic angiotensin Ⅱ (AngⅡ) infusion. Methods and Results By generating a tamoxifen-inducible cardiomyocyte-specific Bmal1 knockout mouse line (cKO) and challenging the mice with transverse aortic constriction or AngⅡ, we found that compared to littermate controls, the cKO mice displayed remarkably increased cardiac hypertrophy and augmented fibrosis both after transverse aortic constriction and AngⅡ induction, as assessed by echocardiographic, gravimetric, histologic, and molecular analyses. Mechanistically, RNA-sequencing analysis of the heart after transverse aortic constriction exposure revealed that the PI3K/AKT signaling pathway was significantly activated in the cKOs. Consistent with the in vivo findings, in vitro study showed that knockdown of Bmal1 in cardiomyocytes significantly promoted phenylephrine-induced cardiomyocyte hypertrophy and triggered fibroblast-to-myofibroblast differentiation, while inhibition of AKT remarkedly reversed the pro-hypertrophy and pro-fibrosis effects of Bmal1 knocking down. Conclusions These results suggest that postnatal deletion of Bmal1 in cardiomyocytes may promote pressure overload-induced cardiac remodeling. Moreover, we identified PI3K/AKT signaling pathway as the potential mechanistic ties between Bmal1 and cardiac remodeling.

Keywords: Bmal1; cardiac remodeling; circadian clock; fibrosis; hypertrophy

DOI: https://doi.org/10.1161/JAHA.121.025021

Cardiovasc Res. 2022 Jun 21. pii: cvac101. [Epub ahead of print]

ULK1 mediated mitophagy prevents pathological cardiac remodelling and heart failure.

Rimpy Dhingra, Lorrie A Kirshenbaum.

The defects in mitochondrial clearance mechanisms can trigger adverse cardiac remodeling and severely impair cardiac performance. A new study identifies Ulk1/Rab9 mediated alternative mitophagy to be important for mitochondrial clearance in heart under pressure overload conditions. Moreover, the defects in ULK1 mediated alternative mitophagy resulted in accumulation of damaged mitochondria, severe hypertrophy, fibrosis, and cardiac dysfunction in response to TAC induced pressure overload. The findings highlight Ulk1/Rab9 mediated alternative mitophagy as a prominent mode of mitophagy and quality control in response to pressure overload hypertrophy.

Keywords: Heart failure; Hypertrophy; Mitochondria; Mitophagy; Pressure-overload

DOI: https://doi.org/10.1093/cvr/cvac101

Int J Mol Sci. 2022 Jun 18. pii: 6809. [Epub ahead of print]23(12):

Derangements and Reversibility of Energy Metabolism in Failing Hearts Resulting from Volume Overload: Transcriptomics and Metabolomics Analyses.

Ying-Chang Tung, Mei-Ling Cheng, Lung-Sheng Wu, Hsiang-Yu Tang, Cheng-Yu Huang, Gwo-Jyh Chang, Chi-Jen Chang.

Derangements in cardiac energy metabolism have been shown to contribute to the development of heart failure (HF). This study combined transcriptomics and metabolomics analyses to characterize the changes and reversibility of cardiac energetics in a rat model of cardiac volume overload (VO) with the creation and subsequent closure of aortocaval fistula. Male Sprague-Dawley rats subjected to an aortocaval fistula surgery for 8 and 16 weeks exhibited characteristics of compensated hypertrophy (CH) and HF, respectively, in echocardiographic and hemodynamic studies. Glycolysis was downregulated and directed to the hexosamine biosynthetic pathway (HBP) and O-linked-N-acetylglucosaminylation in the CH phase and was further suppressed during progression to HF. Derangements in fatty acid oxidation were not prominent until the development of HF, as indicated by the accumulation of acylcarnitines. The gene expression and intermediates of the tricarboxylic acid cycle were not significantly altered in this model. Correction of VO largely reversed the differential expression of genes involved in glycolysis, HBP, and fatty acid oxidation in CH but not in HF. Delayed correction of VO in HF resulted in incomplete recovery of defective glycolysis and fatty acid oxidation. These findings may provide insight into the development of innovative strategies to prevent or reverse metabolic derangements in VO-induced HF.

Keywords: compensated hypertrophy; energy metabolism; heart failure; volume overload

DOI: https://doi.org/10.3390/ijms23126809

Nature. 2022 Jun 22.

Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy.

Mark Chaffin, Irinna Papangeli, Bridget Simonson, Amer-Denis Akkad, Matthew C Hill, Alessandro Arduini, Stephen J Fleming, Michelle Melanson, Sikander Hayat, Maria Kost-Alimova, Ondine Atwa, Jiangchuan Ye, Kenneth C Bedi, Matthias Nahrendorf, Virendar K Kaushik, Christian M Stegmann, Kenneth B Margulies, Nathan R Tucker, Patrick T Ellinor.

Heart failure encompasses a heterogeneous set of clinical features that converge on impaired cardiac contractile function1,2 and presents a growing public health concern. Previous work has highlighted changes in both transcription and protein expression in failing hearts3,4, but may overlook molecular changes in less prevalent cell types. Here we identify extensive molecular alterations in failing hearts at single-cell resolution by performing single-nucleus RNA sequencing of nearly 600,000 nuclei in left ventricle samples from 11 hearts with dilated cardiomyopathy and 15 hearts with hypertrophic cardiomyopathy as well as 16 non-failing hearts. The transcriptional profiles of dilated or hypertrophic cardiomyopathy hearts broadly converged at the tissue and cell-type level. Further, a subset of hearts from patients with cardiomyopathy harbour a unique population of activated fibroblasts that is almost entirely absent from non-failing samples. We performed a CRISPR-knockout screen in primary human cardiac fibroblasts to evaluate this fibrotic cell state transition; knockout of genes associated with fibroblast transition resulted in a reduction of myofibroblast cell-state transition upon TGFβ1 stimulation for a subset of genes. Our results provide insights into the transcriptional diversity of the human heart in health and disease as well as new potential therapeutic targets and biomarkers for heart failure.

DOI: https://doi.org/10.1038/s41586-022-04817-8

Oxid Med Cell Longev. 2022 ;2022 5554290

Paricalcitol Attenuates Metabolic Syndrome-Associated Heart Failure through Enhanced Mitochondrial Fusion.

Hina L Nizami, Parmeshwar B Katare, Pankaj Prabhakar, Ramu Adela, Soumalya Sarkar, Sudheer Arava, Praloy Chakraborty, Subir K Maulik, Sanjay K Banerjee.

Objectives: Transition from cardiac hypertrophy to failure involves adverse metabolic reprogramming involving mitochondrial dysfunction. We have earlier shown that vitamin D deficiency induces heart failure, at least in part, through insulin resistance. However, whether activation of vitamin D receptor (VDR) can attenuate heart failure and underlying metabolic phenotype requires investigation. Thus, we aimed to assess the cardioprotective potential of paricalcitol, a vitamin D receptor-activator, against cardiac hypertrophy and failure in high-fat high-fructose-fed rats.
Methods: Male Sprague Dawley rats were fed control (Con) or high-fat high-fructose (HFHFrD) diet for 20 weeks. After 12 weeks, rats from HFHFrD group were divided into the following: HFHFrD, HFHFrD+P (paricalcitol i.p. 0.08 μg/kg/day) and HFHFrD+E (enalapril maleate i.p. 10 mg/kg/day). Intraperitoneal glucose tolerance test, blood pressure measurement, and 2D echocardiography were performed. Cardiac fibrosis was assessed by Masson's trichrome staining of paraffin-embedded heart sections. Mitochondrial DNA and proteins, and citrate synthase activity were measured in rat hearts. VDR was silenced in H9c2 cardiomyoblasts, and immunoblotting was performed.
Results: Paricalcitol improved glucose tolerance, serum lipid profile, and blood pressure in high-fat high-fructose-fed rats. Paricalcitol reduced cardiac wall thickness and increased ejection fraction in high-fat high-fructose-fed rats but had no effect on perivascular fibrosis. PGC1-α was upregulated in the HFHFrD+P group compared to the HFHFrD group, but there was no significant difference in mitochondrial content. Citrate synthase activity was significantly higher in the HFHFrD+P group compared to the HFHFrD group. Rat hearts of the HFHFrD+P group had significantly higher expression of mitofusins. H9c2 cells with VDR knockdown showed significantly lower expression of Mfn2. Improvement in the HFHFrD+P group was comparable with that in the HFHFrD+E group.
Conclusions: Paricalcitol reverses cardiac dysfunction in rats with metabolic syndrome by enhancing mitochondrial fusion. We demonstrate repurposing potential of the drug currently used in end-stage kidney disease.

DOI: https://doi.org/10.1155/2022/5554290