Elucidating cardioprotective effects of mutant phosphodiesterase 3A

高血压伴短指（HTNB）是一种常染色体显性遗传的高血压。这是一种罕见的综合征，其中血压可以上升超过50毫米汞柱。未经治疗的患者在50岁之前死于中风。我们已经证明HTNB是由磷酸二酯酶3A（PDE 3A）基因的功能获得性突变引起的。高血压是由血管平滑肌细胞失调引起的。令人惊讶的是，经过几十年的高血压HTNB患者和我们的HTNB大鼠模型并没有与典型的高血压引起的心脏损害，如肥大或衰竭。然而，心肌保护的分子机制尚不清楚。他们的阐明不仅将阐明迄今为止未知的PDE 3A在心脏中的功能;他们的理解也可以为治疗和/或预防高血压和高血压诱导的心脏损伤的新方法铺平道路。基于对这些疾病的持续医疗需求，迫切需要创新的概念。全世界有13亿人患有高血压，6400万人患有心力衰竭。因此，该项目的目的是阐明突变体PDE 3A介导的心脏保护作用的机制。由于突变型PDE 3A是过度活跃的，PDE 3A在限定的细胞区室中指导cAMP和cGMP信号，因此主要关注心肌细胞中区室化PDE 3A指导的信号转导的显微镜分析。此外，我们将采用细胞生物学和生物化学方法。

Hypertension with brachydactyly (HTNB) represents an autosomal dominant form of hypertension. It is a rare syndrome, in which the blood pressure can rise by more than 50 mmHg. Untreated patients die of stroke by the age of 50 years. We have shown that HTNB is caused by gain-of-function mutations in the phosphodiesterase 3A (PDE3A) gene. The hypertension is caused by dysregulation of vascular smooth muscle cells. Surprisingly, after decades of hypertension HTNB in patients and our HTNB rat models is not associated with the typical hypertension-induced cardiac damage, such as hypertrophy or failure. However, the molecular mechanisms underlying the cardioprotection are unclear. Their elucidation would not only shed light on so far unknown PDE3A functions in the heart; their understanding could also pave the way to novel approaches for the treatment and/or prevention of hypertension and hypertension-induced cardiac damage. Based on the persistent medical need for these conditions, innovative concepts are urgently required. Worldwide, 1.3 billion people are affected by hypertension and 64 million by heart failure. Therefore, the aim of the proposed project is the elucidation of the mechanisms underlying the mutant PDE3A-mediated cardioprotection. Since mutant PDE3A is hyperactive and PDE3A directs cAMP and cGMP signals in defined cellular compartments, a major focus will be on the microscopic analysis of compartmentalised PDE3A-directed signal transduction in cardiac myocytes. In addition, we will employ cell biological and biochemical approaches.