Browsing by Author "Wu, Yijen L."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability
    (Elsevier, 2022-02-15) Teekakirikul, Polakit; Zhu, Wenjuan; Xu, Xinxiu; Young, Cullen B.; Tan, Tuantuan; Smith, Amanda M.; Wang, Chengdong; Peterson, Kevin A.; Gabriel, George C.; Ho, Sebastian; Sheng, Yi; de Bellaing, Anne Moreau; Sonnenberg, Daniel A.; Lin, Jiuann-huey; Fotiou, Elisavet; Tenin, Gennadiy; Wang, Michael X.; Wu, Yijen L.; Feinstein, Timothy; Devine, William; Gou, Honglan; Bais, Abha S.; Glennon, Benjamin J.; Zahid, Maliha; Wong, Timothy C.; Ahmad, Ferhaan; Rynkiewicz, Michael J.; Lehman, William J.; Keavney, Bernard; Alastalo, Tero-Pekka; Freckmann, Mary-Louise; Orwig, Kyle; Murray, Steve; Ware, Stephanie M.; Zhao, Hui; Feingold, Brian; Lo, Cecilia W.; Pediatrics, School of Medicine
    Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.
  • Thumbnail Image
    Item
    Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction
    (American Heart Association, 2021) Satoh, Taijyu; Wang, Longfei; Espinosa-Diez, Cristina; Wang, Bing; Hahn, Scott A.; Noda, Kentaro; Rochon, Elizabeth R.; Dent, Matthew R.; Levine, Andrea; Baust, Jeffrey J.; Wyman, Samuel; Wu, Yijen L.; Triantafyllou, Georgios A.; Tang, Ying; Reynolds, Mike; Shiva, Sruti; St. Hilaire, Cynthia; Gomez, Delphine; Goncharov, Dmitry A.; Goncharova, Elena A.; Chan, Stephen Y.; Straub, Adam C.; Lai, Yen-Chun; McTiernan, Charles F.; Gladwin, Mark T.; Medicine, School of Medicine
    Background: Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells. Methods: We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress. Results: Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. Conclusions: In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.