Abstract 323: Re-expression of T-type Calcium Current in the Heart Protects from Stress-induced Hypertrophy and Heart Failure
Alterations in intracellular calcium handling are hypothesized to underlie cardiac disease through activating various calcium-dependent signaling pathways. For example, increased calcium influx or enhanced diastolic calcium levels are thought to be prohypertrophic and to contribute to heart failure by activating pathology-inducing signaling pathways. T-type calcium currents (TTCC), which are mainly expressed in the embryonic heart, become re-expressed in adult ventricular myocytes in pathological states, such as cardiac hypertrophy.
[Objective and Methods] To determine if TTCC re-expression induces or enhances cardiac pathology and deleterious signaling we generated transgenic (TG) mice with inducible cardiac-specific expression of the α1G subunit of the T-type calcium channel.
[Results] Two inducible α-MHC-α1G subunit TG lines were obtained. When induced, myocytes from TG mice showed a maximum TTCC (ICa-T) density of −18.3 ± 1.0pA/pF, compared with non-TG littermate values of −0.1 ± 0.02pA/pF. Enhanced TTCC observed in these TG mice also lead to a subtle, but significant down-regulation in L-type calcium current (TG −4.78+/−0.28 vs. non-TG -7.2+/−0.33 pA/pF). Neither TG line showed cardiac hypertrophy at baseline as assessed by heart weight normalized to body weight (HW/BW; mg/g) (5.0 ± 0.1, n = 12 and 4.9 ± 0.1, n = 5 in TG vs 4.9 ± 0.1 in non-TG n = 10), or any effect on cardiac function at 3 month of age. However, and in contrast to our original hypothesis, TG mice showed significantly less increases in HW/BW ratio (5.6 ± 0.1, n = 10 vs 6.9 ± 0.2 n = 11, p < 0.05) and cell surface area (microm2) (281 ± 28, n = 4 vs 415 ± 25, n = 4, p < 0.05) following 2 weeks of transverse aortic constriction (TAC) compared with non-TG mice. Moreover, isoproterenol stimulation induced less hypertrophy in TG mice compared with non-TG controls (HW/BW: 5.9 ± 0.1, n = 7 vs 6.7 ± 0.2 n = 7, p < 0.05). Finally, TG mice continued to show less cardiac hypertrophy after 8 weeks of TAC compared with non-TG controls (HW/BW: 6.3 ± 0.2, n = 5 vs 7.4 ± 0.2 n = 6, p < 0.05), and TG mice showed less reduction in cardiac function as measured by echocardiography.
[Conclusion]Increased TTCC in cardiomyocytes serves as a compensatory alteration that is anti-hypertrophic and possibly protective from heart failure.