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Cardiovascular consequences of KATP overactivity in Cantu syndrome
- Source :
- JCI Insight. 3
- Publication Year :
- 2018
- Publisher :
- American Society for Clinical Investigation, 2018.
-
Abstract
- Cantu syndrome (CS) is characterized by multiple vascular and cardiac abnormalities including vascular dilation and tortuosity, systemic hypotension, and cardiomegaly. The disorder is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits. However, there is little understanding of the link between molecular dysfunction and the complex pathophysiology observed, and there is no known treatment, in large part due to the lack of appropriate preclinical disease models in which to test therapies. Notably, expression of Kir6.1 and SUR2 does not fully overlap, and the relative contribution of KATP GOF in various cardiovascular tissues remains to be elucidated. To investigate pathophysiologic mechanisms in CS we have used CRISPR/Cas9 engineering to introduce CS-associated SUR2[A478V] and Kir6.1[V65M] mutations to the equivalent endogenous loci in mice. Mirroring human CS, both of these animals exhibit low systemic blood pressure and dilated, compliant blood vessels, as well dramatic cardiac enlargement, the effects being more severe in V65M animals than in A478V animals. In both animals, whole-cell patch-clamp recordings reveal enhanced basal KATP conductance in vascular smooth muscle, explaining vasodilation and lower blood pressure, and demonstrating a cardinal role for smooth muscle KATP dysfunction in CS etiology. Echocardiography confirms in situ cardiac enlargement and increased cardiac output in both animals. Patch-clamp recordings reveal reduced ATP sensitivity of ventricular myocyte KATP channels in A478V, but normal ATP sensitivity in V65M, suggesting that cardiac remodeling occurs secondary to KATP overactivity outside of the heart. These SUR2[A478V] and Kir6.1[V65M] animals thus reiterate the key cardiovascular features seen in human CS. They establish the molecular basis of the pathophysiological consequences of reduced smooth muscle excitability resulting from SUR2/Kir6.1–dependent KATP GOF, and provide a validated animal model in which to examine potential therapeutic approaches to treating CS.
- Subjects :
- Male
0301 basic medicine
Cantú syndrome
endocrine system
medicine.medical_specialty
Patch-Clamp Techniques
Vascular smooth muscle
Heart Ventricles
Hypertrichosis
Cardiomegaly
Mice, Transgenic
Vasodilation
Osteochondrodysplasias
Sulfonylurea Receptors
Muscle, Smooth, Vascular
ABCC9
Mice
03 medical and health sciences
KATP Channels
Internal medicine
medicine
Animals
Humans
Myocyte
Myocytes, Cardiac
Gene Knock-In Techniques
Ventricular remodeling
Excitation Contraction Coupling
Ventricular Remodeling
business.industry
General Medicine
medicine.disease
Pathophysiology
Disease Models, Animal
030104 developmental biology
Echocardiography
Gain of Function Mutation
Cardiology
Sulfonylurea receptor
Female
business
Research Article
Subjects
Details
- ISSN :
- 23793708
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....a1374c29f5e9427a10b23a331148c8c2