The cause of altered ionic homeostasis leading to cell death during ischemia and metabolic inhibition is unclear. Hemichannels, which are precursors to gap junctions, are nonselective ion channels that are permeable to molecules of less than M r 1000. We show that hemichannels open upon exposure to calcium-free solutions when they are either heterologously overexpressed in HEK293 cells or endogenously expressed in cardiac ventricular myocytes. In the presence of normal extracellular calcium, hemichannels open during metabolic inhibition. During ischemia and other forms of metabolic inhibition, activation of relatively few hemichannels will seriously compromise the cell's ability to maintain ionic homeostasis, which is an essential step promoting cell death.

At birth, the heart undergoes a critical metabolic switch from a predominant dependence on carbohydrates during fetal life to a greater dependence on postnatal oxidative metabolism. This remains the principle metabolic state throughout life, although pathologic conditions such as heart failure and cardiac hypertrophy reactivate components of the fetal genetic program to increase carbohydrate utilization. Disruption of the ERRgamma gene (Esrrg), which is expressed at high levels in the fetal and postnatal mouse heart, blocks this switch, resulting in lactatemia, electrocardiographic abnormalities, and death during the first week of life. Genomic ChIP-on-chip and expression analysis identifies ERRgamma as both a direct and an indirect regulator of a nuclear-encoded mitochondrial genetic network that coordinates the postnatal metabolic transition. These findings reveal an unexpected and essential molecular genetic component of the oxidative metabolic gene program in the heart and highlight ERRgamma in the study of cardiac hypertrophy and failure.

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Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.

In the mammalian heart, the right ventricle (RV) has a distinct structural and electrophysiological profile compared to the left ventricle (LV). However, the possibility that myocytes from the RV and LV have different contractile properties has not been established. 2+ influx and myocyte shortening were larger in response to the LVendo AP, independent of myocyte subtypes. Evaluation of possible regional differences in myocyte Ca 2+ handling was based on: (i) the current-voltage relation of the Ca 2+ current; (ii) sarcoplasmic reticulum Ca 2+ uptake; and (iii) mRNA expression of important components of the Ca 2+ handling system. None of these were significantly different between RV and LVendo. In contrast, the Ca 2+ -independent K + current, which modulates AP repolarization, was significantly different between RV, LVepi and LVendo. These results suggest that these differences in K + currents can alter AP duration and modulate the [Ca 2+ ] i transient and corresponding contraction. In summary, these findings provide an initial description of regional differences in excitation-contraction coupling in the adult mouse heart. Evidence that the AP waveform is an important causative factor for these differences is presented. In hearts from adult mammals, right (RV) and left (LV) ventricles have distinctive structural and contractile characteristics as well as heterogeneous electrophysiological properties (Katz, 2001). The RV pumps blood into the relatively low-pressure pulmonary vasculature. Accordingly RV chamber pressures are much lower and the workload of the right ventricle (RV) differs significantly from that of the left ventricle (LV). In addition, the mechanical afterload in the right ventricle is significantly smaller. Consistent with these physiological differences, the free wall of the RV is much thinner than that of the LV. Systematic electrophysiological studies have also shown that the mammalian ventricle exhibits a well-defined heterogeneity of AP waveforms. In adult mice and rats, the AP duration (APD) at a fixed heart rate is shorter in the RV than in the LV (Watanabe et al.