Journal
HYPERTENSION
Volume 65, Issue 6, Pages 1288-U228Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.115.05290
Keywords
calcium; CAPON; hypertension; primary dysautonomias; sympathetic nervous system; synaptic transmission
Categories
Funding
- British Heart Foundation (BHF)
- BHF Centre of Research Excellence, Oxford
- British Heart Foundation [PG/11/5/28643, FS/15/8/31155] Funding Source: researchfish
Ask authors/readers for more resources
Genome-wide association studies implicate a variant in the neuronal nitric oxide synthase adaptor protein (CAPON) in electrocardiographic QT variation and sudden cardiac death. Interestingly, nitric oxide generated by neuronal NO synthase-1 reduces norepinephrine release; however, this pathway is downregulated in animal models of cardiovascular disease. Because sympathetic hyperactivity can trigger arrhythmia, is this neural phenotype linked to CAPON dysregulation? We hypothesized that CAPON resides in cardiac sympathetic neurons and is a part of the prediseased neuronal phenotype that modulates calcium handling and neurotransmission in dysautonomia. CAPON expression was significantly reduced in the stellate ganglia of spontaneously hypertensive rats before the development of hypertension compared with agematched Wistar-Kyoto rats. The neuronal calcium current (I-Ca; n= 8) and intracellular calcium transient ([Ca2+](i); n= 16) were significantly larger in the spontaneously hypertensive rat than in Wistar-Kyoto rat (P<0.05). A novel noradrenergic specific vector (Ad. PRSx8-mCherry/CAPON) significantly upregulated CAPON expression, NO synthase-1 activity, and cGMP in spontaneously hypertensive rat neurons without altering NO synthase-1 levels. Neuronal I-Ca and [Ca2+](i) were significantly reduced after CAPON transduction compared with the empty vector. In addition, Ad. PRSx8-mCherry/ CAPON also reduced H-3-norepinephrine release from spontaneously hypertensive rat atria (n=7). NO synthase-1 inhibition (AAAN, 10 mu mol/L; n=6) reversed these effects compared with the empty virus alone. In conclusion, targeted upregulation of CAPON decreases cardiac sympathetic hyperactivity. Moreover, dysregulation of this adaptor protein in sympathetic neurons might further amplify the negative cardiac electrophysiological properties seen with CAPON mutations.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available