Abstract 12556: Cx43 Deficiency Is Associated With Dilated Cardiomyopathy In Old Mice That Can Be Rescued By Genetic Ablation Of Its C-terminal Domain
Cx43 has been shown to be involved in cardiomyocyte functions other than electrical impulse propagation, including mitochondrial respiration and energy metabolism. Heterozygous Cx43 deficient mice (Cx43+/-) show normal impulse propagation and lack pathologic cardiac phenotype in young age. We investigated whether Cx43 deficiency is associated with pathologic cardiac phenotype at advanced age (beyond 18 mo), and whether it may be related to the channel properties of Cx43 hemichannels.
Methods and Results: Mitochondria were isolated from hearts of aged wild-type (Cx43+/+), heterozygous Cx43 deficient (Cx43+/-) and heterozygous Cx43 mice expressing a modified Cx43 isoform with truncated C-terminal domain beyond position 258 that forms hemichannels with impaired gating properties (Cx43K258stop). Complex 1 (malate/glutamate) and complex 2 (succinate/rotenone)-mediated oxygen consumption were studied using a Clark-type electrode before and after addition of ADP. ADP-stimulated respiration was reduced in Cx43+/- mice as compared to Cx43+/+ under complex I substrates (16.43 vs 34.89 nmol O2/min·UCS, p<0.01), and this reduction was corrected in mitochondria with truncated Cx43 (29.17 O2/min·UCS in Cx43K258stop, p=ns), but complex 2-driven respiration was similar in all three genotypes (53.01, 44.50 and 38.91, respectively, p=ns). Two-D echocardiography disclosed increased left ventricular end-diastolic dimension in Cx43+/- mice, as compared to wild-type (4.47 vs 3.78 mm, p<0.01) and reduced fractional shortening (31.5 vs 55.7%, p<0.05) but these changes were not present in Cx43K258stop.
Conclusion: Cx43 deficiency is associated with dilated cardiomyopathy with left ventricular dilatation and reduced systolic function, associated with depressed mitochondrial respiration, manifested at advanced age. C-terminal truncation of Cx43 rescues this pathological phenotype.
- © 2011 by American Heart Association, Inc.