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Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease

机译：磷酸二酯酶9A控制非一氧化氮依赖性cGMP和肥厚性心脏病

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摘要

动物研究表明,"phosphodiesterase type 5A" (PDE5A)的抑制(比如说用"伟哥"来抑制)，能通过防止发生由一氧化氮产生的cGMP的降解来保护心脏不受病理性压力的影响。然而，一氧化氮信号作用在心血管病中经常是被抑制的，这就有可能解释为什么PDE5A的抑制在临床试验中结果令人失望。现在，DavidKass及同事识别出另一个目标，即PDE9A,它针对性地调控与"钠尿肽"耦合在一起的cGMP信号作用，并且是独立于一氧化氮的。他们显示，PDE9A在发生衰竭的人心脏中是上调的，在小鼠身上将其抑制，会逆转事先已经发生的由压力诱导的心脏病。PDE9A抑制剂在人身上似乎能够很好耐受，目前正在有关"神经认知"病的临床试验中受到研究。这项研究所取得的新结果表明，这些抑制剂在治疗心脏病方面也可能会找到用途。%Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease6. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7,8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.
机译：动物研究表明,"phosphodiesterase type 5A" (PDE5A)的抑制(比如说用"伟哥"来抑制)，能通过防止发生由一氧化氮产生的cGMP的降解来保护心脏不受病理性压力的影响。然而，一氧化氮信号作用在心血管病中经常是被抑制的，这就有可能解释为什么PDE5A的抑制在临床试验中结果令人失望。现在，DavidKass及同事识别出另一个目标，即PDE9A,它针对性地调控与"钠尿肽"耦合在一起的cGMP信号作用，并且是独立于一氧化氮的。他们显示，PDE9A在发生衰竭的人心脏中是上调的，在小鼠身上将其抑制，会逆转事先已经发生的由压力诱导的心脏病。PDE9A抑制剂在人身上似乎能够很好耐受，目前正在有关"神经认知"病的临床试验中受到研究。这项研究所取得的新结果表明，这些抑制剂在治疗心脏病方面也可能会找到用途。%Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease6. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7,8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.

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  • 来源
    《Nature》 |2015年第7544期|472-476q2q4|共7页
  • 作者

    Dong I. Lee; Guangshuo Zhu; Takashi Sasaki; Gun-Sik Cho; Nazha Hamdani; Ronald Holewinski; Su-Hyun Jo; Thomas Danner; Manling Zhang; Peter P. Rainer; Djahida Bedja; Jonathan A. Kirk; Mark J. Ranek; Wolfgang R. Dostmann; Chulan Kwon; Kenneth B. Margulies; Jennifer E. Van Eyk; Walter J. Paulus; Eiki Takimoto; David A. Kass;

  • 作者单位

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Advanced Medical Research Laboratories, Research Division, Mitsubishi Tana be Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7,1081 BT Amsterdam, The Netherlands;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA,Heart Institute and Advanced Clinical Biosystems Research Institute, Cedar Sinai Medical Center, 8700 Beverly Blvd, AHSP A9229 Los Angeles, California 90048, USA;

    Department of Physiology, Institute of Bioscience and Biotechnology, BK21 plus Graduate Program, Kangwon National University College of Medicine, Chuncheon 200-701, Korea;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Department of Pharmacology, University of Vermont, Burlington, Vermont 05405, USA;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA,Heart Institute and Advanced Clinical Biosystems Research Institute, Cedar Sinai Medical Center, 8700 Beverly Blvd, AHSP A9229 Los Angeles, California 90048, USA;

    Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7,1081 BT Amsterdam, The Netherlands;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA;

    Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA2015-4-28;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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