HomeCirculation ResearchVol. 133, No. 1In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Originally published22 Jun 2023https://doi.org/10.1161/RES.0000000000000616Circulation Research. 2023;133:2is related toDownregulation of FKBP5 Promotes Atrial ArrhythmogenesisDistinct Roles of DRP1 in Conventional and Alternative Mitophagy in Obesity CardiomyopathyAn ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and AtherosclerosisDistinct Roles of DRP1 in Conventional and Alternative Mitophagy in Obesity Cardiomyopathy (p 6)Download figureDownload PowerPointDRP1 drives mitophagy in heart cells and protects against obesity-induced cardiomyopathyMitochondrial dysfunction, driven by metabolic excess and increased reactive oxygen species, is a feature of obesity related cardiomyopathy. Indeed, mitophagy, the process for breaking down and recycling components of defective mitochondria gets ramped up in mice on a high-fat diet—conventional mitophagy in the initial weeks of such a diet and an alternative form in latter months. Fission of the dysfunctional portions of the mitochondria, controlled by the enzyme DRP1, precedes both types of mitophagy, and now Tong and colleagues show that DRP1 is in fact essential for high-fat diet induced mitophagy and heart protection. In mice fed a high-fat diet, decreased heart function was greatly exacerbated if the animals had a cardiomyocyte-specific deletion of DRP1. In fact, the DRP1-lacking animals were far more likely to die. And, in the DRP1-lacking cardiomyocytes themselves, mitochondrial function, oxygen consumption and mitophagy—both conventional and alternative—were all decreased compared with those seen in control cells. The results thus indicate that DRP1 is crucial for promoting important mitochondrial quality control mechanisms and that boosting the levels of this enzyme could be a way to slow the progression of obesity-related cardiomyopathy.An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis (p 25)Download figureDownload PowerPointAbe et al investigate the molecular basis of myeloid cell senescence in atherosclerotic plaque development.Atherosclerosis gets worse with age. Indeed, aging cells—specifically myeloid cells (MCs) exhibiting senescence-associated secretory phenotype (SASP)—are known to contribute to the initiation of atherosclerosis. Both MC SASP and atherosclerosis have been linked to phosphorylation of the signaling factor ERK5 (at serine 496) prompting Abe and colleagues to investigate the role of this factor in more detail. They engineered mice to express a version of ERK5 incapable of S496 phosphorylation and then gave these animals and control mice a high-fat diet for several weeks. While the test and control mice had similar blood lipid levels, the test animals had far less severe atherosclerosis and their plaque and bone marrow MCs showed less evidence of SASP. Interestingly, the control MCs but not the test cells also exhibited senescence-associated stemness (SAS)—a senescence induced stem cell-like proliferative state—which may explain the abundant production of MCs seen in plaques. The team went on to show that transcription factors NRF2 and AHR are key molecular players in ERK5’s senescence- and plaque-promoting activities, and thus have provided insights, and possible targets, for mitigating MC senescence as well as atherosclerosis.Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling (p e1)Download figureDownload PowerPointWang et al determine how loss of FKBP5 leads to development of atrial fibrillation.Atrial fibrillation (AF) is the most common form of arrhythmia and is characterized by extremely fast, irregular beats emanating from the heart’s upper chambers. Symptoms may be episodic, lasting just minutes or hours, or can develop into chronic persistent arrhythmia requiring treatment. A recent transcriptome analysis of patient and control atrial tissue revealed downregulation of FKBP5—a co-chaperone involved in protein folding and trafficking—in patients, and now Wang and colleagues show that this suppression is not merely correlative. They generated mice with a cardiomyocyte-specific FKBP5 deficiency and showed the animals were more prone to inducible AF than their control counterparts. Altered action potentials of the animals’ cardiomyocytes were shown to be due to increased expression of the ion transporter NCX1, and the team went on to show that FKBP5 ordinarily inhibits NCX1 expression indirectly by blocking the activity of transcription factor HIF-1, which targets the gene encoding the transporter. By normalizing the level of HIF-1α in the FKBP5 deficient mice, the team were able to prevent the arrhythmia susceptibility. Together the results suggest that boosting levels of FKBP5 or normalizing levels of HIF-1α may be strategies for treating chronic AF. eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesDownregulation of FKBP5 Promotes Atrial ArrhythmogenesisXiaolei Wang, et al. Circulation Research. 2023;133:e1-e16Distinct Roles of DRP1 in Conventional and Alternative Mitophagy in Obesity CardiomyopathyMingming Tong, et al. Circulation Research. 2023;133:6-21An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and AtherosclerosisJun-ichi Abe, et al. Circulation Research. 2023;133:25-44 June 23, 2023Vol 133, Issue 1 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000616PMID: 37347833 Originally publishedJune 22, 2023 PDF download Advertisement