Browsing by Author "Yang, Qing"

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    Protein Kinase A Is a Master Regulator of Physiological and Pathological Cardiac Hypertrophy
    (American Heart Association, 2024) Bai, Yingyu; Zhang, Xiaoying; Li, Ying; Qi, Fei; Liu, Chong; Ai, Xiaojie; Tang, Mingxin; Szeto, Christopher; Gao, Erhe; Hua, Xiang; Xie, Mingxing; Wang, Xuejun; Tian, Ying; Chen, Yongjie; Huang, Guowei; Zhang, Junping; Xiao, Weidong; Zhang, Lili; Liu, Xueyuan; Yang, Qing; Houser, Steven R.; Chen, Xiongwen; Pediatrics, School of Medicine
    Background: The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear. Methods: Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice. Results: (1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca2+ influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3β signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival. Conclusions: Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.
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    Understanding Onset, Dynamic Transitions, and Associated Inequality Risk Factors for Adverse Posttraumatic Neuropsychiatric Sequelae After Trauma Exposure
    (American Psychiatric Association, 2024-11-06) Lee, Chiyoung; House, Stacey L.; Beaudoin, Francesca L.; Neylan, Thomas C.; Clifford, Gari D.; Linnstaedt, Sarah D.; Germine, Laura T.; Rauch, Scott L.; Haran, John P.; Storrow, Alan B.; Lewandowski, Christopher; Musey, Paul I., Jr.; Hendry, Phyllis L.; Sheikh, Sophia; Punches, Brittany E.; Swor, Robert A.; Hudak, Lauren A.; Pascual, Jose L.; Seamon, Mark J.; Harris, Erica; Pearson, Claire; Peak, David A.; Domeier, Robert M.; Rathlev, Niels K.; O'Neil, Brian J.; Sergot, Paulina; Sanchez, Leon D.; Bruce, Steven E.; Sheridan, John F.; Harte, Steven E.; Koenen, Karestan C.; Kessler, Ronald C.; McLean, Samuel A.; Yang, Qing; An, Xinming; Emergency Medicine, School of Medicine
    Objective: Several gaps remain in the understanding of the onset, dynamic transitions, and associated risk factors of adverse posttraumatic neuropsychiatric sequelae (APNS) in the acute post-trauma window. Based on serial assessments of symptoms from a large cohort study, we identified homogeneous statuses across multiple APNS symptom domains and investigated the dynamic transitions among these statuses during the first 2 months after trauma exposure. Furthermore, we studied how symptom onset and transitions are affected by equity-relevant characteristics. Methods: The analysis was based on 2557 participants enrolled in the Advancing Understanding of RecOvery afteR traumA (AURORA). APNS symptoms comprised pain, depression, sleep discontinuity, nightmares, avoidance, re-experience, anxiety, hyperarousal, somatic symptoms, and mental fatigue. We identified the homogeneous status of APNS symptoms at baseline, 1 month, and 2 months, and explored transition probabilities among these statuses using latent transition analysis. Equity-relevant characteristics included gender, race, education, family income, childhood trauma, and area deprivation. Results: Three homogeneous statuses-low-, moderate-, and severe-symptom-were identified. While the majority of trauma survivors with severe- or moderate-symptom status maintained the same status over time, some transitioned to a less severe symptom status, particularly within the first month. Specifically, females, non-whites, and those with higher childhood trauma were associated with a decreased likelihood of transitioning to a less severe symptom status. From one to 2 months, lower income was associated with a decreased likelihood of transitioning from moderate-to low-symptom status. Conclusions: The findings can inform early intervention strategies for APNS, potentially reducing health disparities among trauma survivors.