A CALCIUM DEPENDENT MODEL OF HEART FAILURE: CHARACTERIZATION AND MECHANISMS TOWARDS PREVENTION
The L-type voltage dependent calcium channel (L-VDCC) is the main entry port, in cardiomyocytes, for calcium, an important intracellular ion. This dissertation centers on a mouse model with a cardiac-specific overexpression of the pore subunit (alpha1C) of the L-VDCC, which displays a 50% increase in calcium entry, cardiac hypertrophy and progression to failure (HF). In vivo, ex vivo and in vitro techniques were utilized to describe this model and several double cross models, generated by breeding our mouse (alpha1C) with other genetically altered mice.The characterization of this model revealed interesting biophysical features of the calcium channel (single channel behavior). During the phase prior to failure (adaptive), the channels are significantly less active than normal. During the HF phase (maladaptive), they are more active. These characteristics may be due to differences in levels of auxiliary subunits of the calcium channel (significantly decreased in the adaptive phase vs. significantly increased in the maladaptive phase). Changes during the adaptive phase could be an accommodative mechanism restricting the amplitude of the calcium current. In the failing stage, the channels become more active than normal cardiomyocytes, resembling those characterized in human HF. This mouse model manages to alter calcium cycling through an up-regulation of the Na+/Ca2+ exchanger, preventing high diastolic calcium during the adaptive phase. Despite this apparently accommodative change, this model fails to maintain normal calcium homeostasis. In the maladaptive phase, the cardiomyocytes exhibit increased diastolic calcium levels, with increased sarcoplasmic reticulum (SR) calcium load and calcium transient amplitude.Two of the double cross lines (with genetic alterations to the alpha1C) gave a partial rescue of the phenotype: a 50% reduction of the Na+/Ca2+ levels and ablation of the phosphatase, calcineurin. Another of these hybrid mouse models, with combined overexpression of the calcium channel and the SR ATPase 1a, demonstrated calcium induced arrhythmias, possibly causing sudden cardiac death. These results suggest the use of calcium channel subunit modulation as a possible therapeutic approach for the treatment of HF, the necessity for tight control of SR calcium load and the relevance of arrhythmias in underlying cardiac dysfunction.
School:University of Cincinnati
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:l type voltage dependent calcium channel heart failure homeostasis electrophysiology cardiac arrhythmias
Date of Publication:01/01/2005