ABSTRACT
The prohormone chromogranin A (CHGA) is ubiquitously found in vesicles of adrenal chromaffin cells and adrenergic neurons, and it is processed to the hypotensive hormone peptide catestatin (CST). Both CHGA and CST regulate blood pressure and cardiac function. This study addresses their role in cardiac electrical activity. We have generated two genomically "humanized" transgenic mouse strains (Tg31CHGA+/+; Chga-/- (HumCHGA31) and Tg19CHGA+/+; Chga-/- (HumCHGA19)) with varied CHGA expression and the ability to rescue the Chga-/- phenotype (hypertensive, hyperadrenergic with dilated cardiomyopathy). The normotensive HumCHGA31 mice express CHGA at levels comparable to wild-type. In contrast, the hypertensive HumCHGA19 mice have low levels of CHGA. EKG recordings revealed that the QT interval, R-amplitude, and QRS time-voltage integral are markedly longer in HumCHGA19 compared to wild-type and HumCHGA31 mice. These differences are accompanied by increased heart rate and QT variability, indicating that ventricular assault happens in a status of low levels of circulating CST.
Subject(s)
Arrhythmias, Cardiac/metabolism , Chromogranin A/metabolism , Heart Conduction System/physiopathology , Hypertension/metabolism , Action Potentials , Animals , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/physiopathology , Blood Pressure , Chromogranin A/blood , Chromogranin A/deficiency , Chromogranin A/genetics , Disease Models, Animal , Electrocardiography , Genotype , Heart Rate , Humans , Hypertension/genetics , Hypertension/physiopathology , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Peptide Fragments/blood , Phenotype , Time FactorsABSTRACT
Chromogranin A (CHGA/Chga) has been implicated in the genesis of systemic hypertension and consequent cardiac abnormalities. Catestatin (CST) (human CHGA(352-372)) replacement reduces blood pressure elevation and increases baroreflex sensitivity in Chga knockout (KO) mice. Because of the dampened baroreflex sensitivity, we reasoned that KO mice would display altered heart rate variability (HRV). Thus, we evaluated beat-to-beat measurements in HRV in wild-type (WT) and KO mice, before and after CST replacement. HR dynamics were evaluated by bipolar Einthoven electrocardiogram, with deconvolution into time and frequency domains, as well as Lorenz nonlinear return analyses. At baseline, HR was higher [444 +/- 24 beats per minute (bpm)] in KO compared with WT (330 +/- 18 bpm) mice. The total power in the HRV spectra was substantially diminished in KO animals. CST increased total power but only in KO mice. Each time-domain parameter was substantially lower in KO compared with WT mice, and the CST in the KO group could reverse the differences. Lorenz analysis revealed reductions in S1 (short axis perpendicular to the line of identity in the ellipse) and S2 (long axis along the line of identity in the ellipse) in KO animals, indicating that regulation of HRV is diminished in the parasympathetic and sympathetic domains. CST replacement caused restoration of both S1 and S2, in the KO group. These data suggest that Chga has a profound effect on autonomic tone to the heart and that its CST fragment is responsible for such actions. The results suggest future strategies for intervention in cardiovascular disorders accompanied by adverse HRV profiles.
