Browsing by Author "Warren, Junco S."

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    Cardiovascular aging: from cellular and molecular changes to therapeutic interventions
    Vakka, Angeliki; Warren, Junco S.; Drosatos, Konstantinos (OAE Publishing, 2023-07-01)
    Progressive age-induced deterioration in the structure and function of the cardiovascular system involves cardiac hypertrophy, diastolic dysfunction, myocardial fibrosis, arterial stiffness, and endothelial dysfunction. These changes are driven by complex processes that are interconnected, such as oxidative stress, mitochondrial dysfunction, autophagy, inflammation, fibrosis, and telomere dysfunction. In recent years, the advances in research of cardiovascular aging, including the wide use of animal models of cardiovascular aging, elucidated an abundance of cell signaling pathways involved in these processes and brought into sight possible interventions, which span from pharmacological agents, such as metformin, sodium-glucose cotransporter 2-inhibitors, rapamycin, dasatinib and quercetin, to lifestyle changes.
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    PERM1 regulates energy metabolism in the heart via ERR alpha/PGC-1 alpha axis
    Oka, Shin-ichi I.; Sreedevi, Karthi; Shankar, Thirupura S.; Yedla, Shreya; Arowa, Sumaita; James, Amina; Stone, Kathryn G.; Olmos, Katia; Sabry, Amira D.; Horiuchi, Amanda; Cawley, Keiko M.; O'very, Sean A.; Tong, Mingming; Byun, Jaemin; Xu, Xiaoyong; Kashyap, Sanchita; Mourad, Youssef; Vehra, Omair; Calder, Dallen; Lunde, Ty; Liu, Tong; Li, Hong; Mashchek, J. Alan; Cox, James; Saijoh, Yukio; Drakos, Stavros G.; Warren, Junco S. (Frontiers, 2022-11-07)
    Aims: PERM1 is a striated muscle-specific regulator of mitochondrial bioenergetics. We previously demonstrated that PERM1 is downregulated in the failing heart and that PERM1 positively regulates metabolic genes known as targets of the transcription factor ERRα and its coactivator PGC-1α in cultured cardiomyocytes. The aims of this study were to determine the effect of loss of PERM1 on cardiac function and energetics using newly generated Perm1-knockout (Perm1–/–) mice and to investigate the molecular mechanisms of its transcriptional control. Methods and results: Echocardiography showed that ejection fraction and fractional shortening were lower in Perm1–/– mice than in wild-type mice (both p < 0.05), and the phosphocreatine-to-ATP ratio was decreased in Perm1–/– hearts (p < 0.05), indicating reduced contractile function and energy reserves of the heart. Integrated proteomic and metabolomic analyses revealed downregulation of oxidative phosphorylation and upregulation of glycolysis and polyol pathways in Perm1–/– hearts. To examine whether PERM1 regulates energy metabolism through ERRα, we performed co-immunoprecipitation assays, which showed that PERM1 bound to ERRα in cardiomyocytes and the mouse heart. DNA binding and reporter gene assays showed that PERM1 was localized to and activated the ERR target promoters partially through ERRα. Mass spectrometry-based screening in cardiomyocytes identified BAG6 and KANK2 as potential PERM1’s binding partners in transcriptional regulation. Mammalian one-hybrid assay, in which PERM1 was fused to Gal4 DNA binding domain, showed that the recruitment of PERM1 to a gene promoter was sufficient to activate transcription, which was blunted by silencing of either PGC-1α, BAG6, or KANK2. Conclusion: This study demonstrates that PERM1 is an essential regulator of cardiac energetics and function and that PERM1 is a novel transcriptional coactivator in the ERRα/PGC-1α axis that functionally interacts with BAG6 and KANK2.
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    Protective mitochondrial fission induced by stress-responsive protein GJA1-20k
    Shimura, Daisuke; Nuebel, Esther; Baum, Rachel; Valdez, Steven E.; Xiao, Shaohua; Warren, Junco S.; Palatinus, Joseph A.; Hong, TingTing; Rutter, Jared; Shaw, Robin M. (eLife, 2021-10-05)
    The Connexin43 gap junction gene GJA1 has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection. Here, using human cells and mice, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 s of GJA1-20k recruitment of actin. Interestingly, GJA1-20k mediated fission is independent of canonical Dynamin-Related Protein 1 (DRP1). We find that GJA1-20k-induced smaller mitochondria have decreased reactive oxygen species (ROS) generation and, in hearts, provide potent protection against ischemia-reperfusion injury. The results indicate that stress responsive internally translated GJA1-20k stabilizes polymerized actin filaments to stimulate non-canonical mitochondrial fission which limits ischemic-reperfusion induced myocardial infarction.
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    Sigma non-opioid receptor 1 is a potential therapeutic target for long QT syndrome
    Song, LouJin; Bekdash, Ramsey; Morikawa, Kumi; Quejada, Jose R.; Klein, Alison D.; Aina-Badejo, Danielle; Yoshida, Kazushige; Yamamoto, Hannah E.; Chalan, Amy; Yang, Risako; Patel, Achchhe; Sirabella, Dario; Lee, Teresa M.; Joseph, Leroy C.; Kawano, Fuun; Warren, Junco S.; Soni, Rajesh K.; Morrow, John P.; Yazawa, Masayuki (Springer, 2022-02-17)
    Some missense gain-of-function mutations in CACNA1C gene, encoding calcium channel CaV1.2, cause a life-threatening form of long QT syndrome named Timothy syndrome, with currently no clinically-effective therapeutics. Here we report that pharmacological targeting of sigma non-opioid intracellular receptor 1 (SIGMAR1) can restore electrophysiological function in iPSC-derived cardiomyocytes generated from patients with Timothy syndrome and two common forms of long QT syndrome, type 1 (LQTS1) and 2 (LQTS2), caused by missense trafficking mutations in potassium channels. Electrophysiological recordings demonstrate that an FDA-approved cough suppressant, dextromethorphan, can be used as an agonist of SIGMAR1, to shorten the prolonged action potential in Timothy syndrome cardiomyocytes and human cellular models of LQTS1 and LQTS2. When tested in vivo, dextromethorphan also normalized the prolonged QT intervals in Timothy syndrome model mice. Overall, our study demonstrates that SIGMAR1 is a potential therapeutic target for Timothy syndrome and possibly other inherited arrhythmias such as LQTS1 and LQTS2.
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    YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload
    Kashihara, Toshihide; Mukai, Risa; Oka, Shin-ichi I.; Zhai, Peiyong; Nakada, Yasuki; Yang, Zhi; Mizushima, Wataru; Nakahara, Tsutomu; Warren, Junco S.; Abdellatif, Maha; Sadoshima, Junichi (American Society for Clinical Investigation, 2022-03-15)
    The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is activated and mediates compensatory cardiac hypertrophy in response to acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn caused accumulation of intermediates and metabolites of the glycolytic, auxiliary, and anaplerotic pathways during acute PO. Cardiac hypertrophy was inhibited and heart failure was exacerbated in mice with YAP haploinsufficiency in the presence of acute PO. However, normalization of GLUT1 rescued the detrimental phenotype. PO induced the accumulation of glycolytic metabolites, including l-serine, l-aspartate, and malate, in a YAP-dependent manner, thereby promoting cardiac hypertrophy. YAP upregulated the GLUT1 gene through interaction with TEA domain family member 1 (TEAD1) and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy through activation of the Warburg effect.