Elucidating cardioprotective effects of mutant phosphodiesterase 3A

• Applicants: Privatdozent Dr. Enno Klußmann; Professor Dr. Viacheslav Nikolaev
• Subject Area: Pharmacology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531907792

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.

• DFG Programme: Research Grants