Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter.
Healthy cardiovascular function relies on a balanced and responsive integration of noradrenergic and cholinergic innervation of the heart. High-affinity choline uptake by cholinergic terminals is pivotal for efficient ACh production and release. To date, the cardiovascular impact of diminished choline transporter (CHT) expression has not been directly examined, largely due to the transporter's inaccessibility in vivo. Here, we describe findings from cardiovascular experiments using transgenic mice that bear a CHT genetic deficiency. Whereas CHT knockout (CHT(-/-)) mice exhibit early postnatal lethality, CHT heterozygous (CHT(+/-)) mice survive, grow, and reproduce normally and exhibit normal spontaneous behaviors. However, the CHT(+/-) mouse heart displays significantly reduced levels of high-affinity choline uptake accompanied by significantly reduced levels of ACh. Telemeterized recordings of cardiovascular function in these mice revealed tachycardia and hypertension at rest. After treadmill exercise, CHT(+/-) mice exhibited slower heart rate recovery, consistent with a diminished cholinergic reserve, a contention validated through direct vagal nerve stimulation. Echocardiographic and histological experiments revealed an age-dependent decrease in fractional shortening, increased left ventricular dimensions, and increased ventricular fibrosis, consistent with ventricular dysfunction. These cardiovascular phenotypes of CHT(+/-) mice encourage an evaluation of humans bearing reduced CHT expression for their resiliency in maintaining proper heart function as well as risk for cardiovascular disease.
English
Brett A
BA
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548, USA.
Appalsamy
Martin
M
Diedrich
Andre
A
Ruggiero
Alicia M
AM
Lund
David
D
Wright
Jane
J
Keller
Nancy R
NR
Louderback
Katherine M
KM
Robertson
David
D
Blakely
Randy D
RD
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001341:Autonomic Nervous System / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002794:Choline / Q000378:metabolism*; D004452:Echocardiography; D006339:Heart Rate / Q000235:genetics; D006973:Hypertension / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010805:Physical Conditioning, Animal; D013610:Tachycardia / Q000235:genetics / Q000378:metabolism*; D013686:Telemetry; D018754:Ventricular Dysfunction / Q000235:genetics / Q000378:metabolism*
C501512:CHT1 protein, rat; D027682:Cation Transport Proteins; D002794:Choline