The F-BAR Protein NOSTRIN Dictates the Localization of the Muscarinic M3 Receptor and Regulates Cardiovascular Function
Rationale: Endothelial dysfunction is an early event in cardiovascular disease and characterized by reduced production of nitric oxide. The F-BAR protein NOSTRIN is an interaction partner of endothelial nitric oxide synthase and modulates its subcellular localization but the role of NOSTRIN in pathophysiology in vivo is unclear.
Objective: We analyzed the consequences of deleting the NOSTRIN gene in endothelial cells on nitric oxide production and cardiovascular function in vivo using NOSTRIN knockout mice.
Methods and Results: The levels of nitric oxide and cGMP were significantly reduced in mice with endothelial cell-specific deletion of the NOSTRIN gene resulting in diastolic heart dysfunction. Additionally, systemic blood pressure was increased and myograph measurements indicated an impaired acetylcholine-induced relaxation of isolated aortic rings as well as resistance arteries. We found that the muscarinic acetylcholine receptor M3R interacted directly with NOSTRIN and the latter was necessary for correct localization of the M3R at the plasma membrane in murine aorta. In the absence of NOSTRIN the acetylcholine-induced increase in intracellular Ca2+ in primary endothelial cells was abolished. Moreover, the activating phosphorylation and Golgi translocation of endothelial nitric oxide synthase in response to the M3R agonist carbachol were diminished.
Conclusions: NOSTRIN is crucial for the localization and function of the M3R as well as nitric oxide production. The loss of NOSTRIN in mice leads to endothelial dysfunction, increased blood pressure and diastolic heart failure.
- BAR domain protein
- G-protein coupled receptor
- animal model cardiovascular disease
- endothelial nitric oxide synthase
- G proteins
- Received February 5, 2015.
- Revision received July 9, 2015.
- Accepted July 10, 2015.