Role of T-type calcium channel subunits in post-myocardial infarction remodelling probed with genetically engineered
Khai Le Quang1, Patrice Naud, Xiao-Yan Qi
1Research Center and Departments of Medicine, Université de Montréal and Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, Canada.
Aims:
Previous studies suggested that T-type Ca(2+)-current (I(CaT))-blockers improve cardiac remodelling, but all available I(CaT)-blockers have non-specific actions on other currents and/or functions. To clarify the role of I(CaT) in cardiac remodelling, we studied mice with either of the principal cardiac I(CaT)-subunits (Cav3.1 or Cav3.2) knocked out.
Methods And Results:
Adult male Cav3.1- or Cav3.2-knockout (Cav3.1(-/-), Cav3.2(-/-)) mice and respective wild-type (WT) littermate controls were subjected to left anterior descending coronary artery ligation to create myocardial infarction (MI). Echocardiography and programmed electrical stimulation were performed at baseline and 4 weeks post-MI. At baseline, Cav3.1(-/-) mice had slowed heart rates and longer PR intervals vs. WT, but no other electrophysiological and no haemodynamic differences. Cav3.2(-/-) showed no differences vs. WT. Contractile indices (left ventricular fractional shortening and ejection fraction) decreased more post-MI in Cav3.1(-/-) mice than in Cav3.1(+/+) (e.g. by 34 and 29% for WT; 50 and 45% for Cav3.1(-/-), respectively; P < 0.05 for each). Cav3.1(-/-) mice had increased ventricular tachycardia (VT) inducibility post-MI (9 of 11, 82%) vs. WT (3 of 10, 30%; P < 0.05). Cav3.2(-/-) mice were not different in cardiac function or VT inducibility vs. WT. Quantitative polymerase chain reaction showed that Cav3.1 is the major I(CaT)-subunit and that no compensatory Cav3.2 up-regulation occurs in Cav3.1(-/-) mice. Cav3.1(-/-) and Cav3.2(-/-) mice had no mRNA expression for the knocked-out gene, at baseline or post-MI.
Conclusion:
Our findings suggest that, contrary to suggestions from previous studies with (imperfectly selective) pharmacological agents having T-type Ca(2+)-channel-blocking actions, elimination of Cav3.1 expression leads to impaired cardiac function and enhanced arrhythmia vulnerability post-MI, whereas Cav3.2 elimination has no effect.
Insights
Eliminating the Cav3.1 subunit impairs cardiac function and increases arrhythmia risk after myocardial infarction (MI). In contrast, removing the Cav3.2 subunit has no significant effect on cardiac remodeling or vulnerability to arrhythmias.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Ion Channel Function
Background:
- T-type Ca(2+) current (I(CaT)) blockers were suggested to improve cardiac remodeling.
- Existing I(CaT) blockers lack specificity, potentially confounding previous findings.
- The specific roles of cardiac I(CaT) subunits (Cav3.1 and Cav3.2) in cardiac remodeling remain unclear.
Purpose of the Study:
- To elucidate the distinct roles of Cav3.1 and Cav3.2 subunits in cardiac remodeling post-myocardial infarction (MI).
- To investigate the impact of genetic ablation of Cav3.1 or Cav3.2 on cardiac function and electrophysiological stability following MI.
Main Methods:
- Generation and characterization of Cav3.1-knockout (Cav3.1(-/-)) and Cav3.2-knockout (Cav3.2(-/-)) mice.
- Induction of myocardial infarction (MI) via left anterior descending coronary artery ligation.
- Assessment of cardiac function (echocardiography) and arrhythmia inducibility (programmed electrical stimulation) at baseline and 4 weeks post-MI.
Main Results:
- Cav3.1(-/-) mice exhibited impaired contractile function (reduced fractional shortening and ejection fraction) and increased ventricular tachycardia (VT) inducibility post-MI compared to wild-type controls.
- Cav3.2(-/-) mice showed no significant differences in cardiac function or VT inducibility compared to wild-type littermates.
- Quantitative PCR confirmed Cav3.1 as the predominant cardiac I(CaT) subunit, with no compensatory upregulation of Cav3.2 in Cav3.1(-/-) mice.
Conclusions:
- Cav3.1 plays a critical role in maintaining cardiac function and stability post-MI.
- Elimination of Cav3.1 exacerbates cardiac dysfunction and arrhythmia vulnerability after ischemic injury.
- Cav3.2 is not essential for cardiac remodeling or arrhythmia control in the context of MI.
