• Re-Expression of T-Type Calcium Channels Minimally Affects Cardiac Contractility and Activates Pro-Survival Signaling Pathways in the Myocardium

      Houser, Steven R.; Autieri, Michael V.; Eguchi, Satoru; Force, Thomas; Sabri, Abdelkarim (Temple University. Libraries, 2010)
      The role of T-type calcium channels (TTCCs) in the heart is unclear. TTCCs are transiently expressed throughout the neonatal heart during a period of rapid cardiac development. A few weeks postnatally, TTCCs are no longer found in ventricular myocytes (VMs) and calcium influx via TTCCs (ICa,T) is only detected in the SA node and Purkinje system. However, pathologic cardiac stress is associated with re-expression of TTCCs in VMs. Whether ICa,T in this setting promotes cardiac growth or exacerbates cardiac function is a topic of debate. The focus of this thesis work was to examine the effect of TTCC re-expression in the normal and diseased myocardium. Our experiments were performed in a transgenic mouse model with inducible, cardiac-specific expression of α1G TTCCs. While both the α1G and α1H TTCC subtypes re-appear during cardiac disease, we specifically evaluated the effects of α1G TTCCs since mRNA levels of this TTCC subtype are markedly elevated during cardiac pathology. We found that transgenic mice with α1G overexpression had robust ICa,T with biophysical properties similar to those published in previous studies. α1G mice had a small increase in cardiac function and showed no evidence of cardiac histopathology or increased mortality. These findings were in contrast to the phenotype of transgenic mice with augmented L-type calcium channel (LTCC) activity secondary to overexpression of the β2a regulatory subunit. While the magnitude of calcium influx in α1G and β2a VMs was similar, we found that cardiac contractility of β2a mice was significantly greater than α1G mice. Also, β2a mice had significant cardiac fibrosis, myocyte death, and premature lethality compared to the benign phenotype of α1G mice. We showed that the phenotypic differences are likely related to the differential spatial localization of T- and LTCCs. Whereas α1G TTCCs were principally localized to the surface sarcolemma, LTCCs were primarily found in the transverse tubules in close proximity to the sites of sarcoplasmic reticulum calcium release. We evaluated the effect of TTCC expression during cardiac disease by inducing myocardial infarction (MI) in α1G mice. Acutely (1-week post MI), α1G mice showed similar worsening of cardiac function and mortality rates compared to control post-infarct mice. However, α1G hearts had smaller infarct sizes which correlated with increased Akt and NFAT activation in α1G than control hearts. After chronic heart failure, i.e. 7- weeks post-infarction, α1G hearts had significant hypertrophic response as determined by increased HW/BW ratio, myocyte cross-sectional area, as well as NFAT and Akt activity. Finally, α1G mice had a small survival benefit than control mice, which while statistically non-significant, suggests that TTCC re-expression does not exacerbate cardiac function as hypothesized by some investigators. We conclude that TTCCs play a minimal role in cardiac function and activate pro-survival signaling pathways in the myocardium.