title: Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation.
abstract: Renin-angiotensin (RAS) system activation is associated with an increased risk of sudden death. Previously, we used cardiac-restricted angiotensin-converting enzyme (ACE) overexpression to construct a mouse model of RAS activation. These ACE 8/8 mice die prematurely and abruptly. Here, we have investigated cardiac electrophysiological abnormalities that may contribute to early mortality in this model. In ACE 8/8 mice, surface ECG voltages are reduced. Intracardiac electrograms showed atrial and ventricular potential amplitudes of 11% and 24% compared with matched wild-type (WT) controls. The atrioventricular (AV), atrio-Hisian (AH), and Hisian-ventricular (HV) intervals were prolonged 2.8-, 2.6-, and 3.9-fold, respectively, in ACE 8/8 vs. WT mice. Various degrees of AV nodal block were present only in ACE 8/8 mice. Intracardiac electrophysiology studies demonstrated that WT and heterozygote (HZ) mice were noninducible, whereas 83% of ACE 8/8 mice demonstrated ventricular tachycardia with burst pacing. Atrial connexin 40 (Cx40) and connexin 43 (Cx43) protein levels, ventricular Cx43 protein level, atrial and ventricular Cx40 mRNA abundances, ventricular Cx43 mRNA abundance, and atrial and ventricular cardiac Na(+) channel (Scn5a) mRNA abundances were reduced in ACE 8/8 compared with WT mice. ACE 8/8 mice demonstrated ventricular Cx43 dephosphorylation. Atrial and ventricular L-type Ca(2+) channel, Kv4.2 K(+) channel alpha-subunit, and Cx45 mRNA abundances and the peak ventricular Na(+) current did not differ between the groups. In isolated heart preparations, a connexin blocker, 1-heptanol (0.5 mM), produced an electrophysiological phenotype similar to that seen in ACE 8/8 mice. Therefore, cardiac-specific ACE overexpression resulted in changes in connexins consistent with the phenotype of low-voltage electrical activity, conduction defects, and induced ventricular arrhythmia. These results may help explain the increased risk of arrhythmia in states of RAS activation such as heart failure.
authors.affiliation: Division of Cardiology, Atlanta VA Medical Center, 1670 Clairmont Road, Atlanta, GA 30033, USA.
authors.forename: Vijaykumar S
authors.initials: VS
authors.lastname: Kasi
authors.forename: Hong D
authors.initials: HD
authors.lastname: Xiao
authors.forename: Lijuan L
authors.initials: LL
authors.lastname: Shang
authors.forename: Shahriar
authors.initials: S
authors.lastname: Iravanian
authors.forename: Jonathan
authors.initials: J
authors.lastname: Langberg
authors.forename: Emily A
authors.initials: EA
authors.lastname: Witham
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jiao
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Gallego
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Bernstein
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000818:Animals; D017630:Connexins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006327:Heart Block / Q000503:physiopathology*; D006329:Heart Conduction System / Q000503:physiopathology*; D051379:Mice; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000503:physiopathology*; D015854:Up-Regulation
chemical_list: D017630:Connexins; D007703:Peptidyl-Dipeptidase A