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Cardiac Overexpression of S100A6 Attenuates Cardiomyocyte Apoptosis and Reduces Infarct Size After Myocardial
Azadeh Mofid1, Nadav S Newman1, Paul J H Lee1
1Division of Cardiology, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Ontario, Canada.
Insights
S100A6 gene therapy shows promise for acute myocardial infarction. Overexpressing S100A6 reduced cardiac damage and improved survival after ischemia-reperfusion injury in preclinical models.
Area of Science:
- Cardiology
- Molecular Biology
- Gene Therapy
Background:
- S100A6, an EF-hand calcium-binding protein, is implicated in cardiac function.
- Transgenic mice overexpressing S100A6 exhibit reduced cardiac hypertrophy, fibrosis, and apoptosis post-myocardial infarction.
- These findings suggest S100A6 as a potential therapeutic target for acute myocardial infarction.
Purpose of the Study:
- To investigate the therapeutic potential of S100A6 gene therapy for acute myocardial ischemia-reperfusion injury.
Main Methods:
- In vitro studies assessed S100A6 effects on rat neonatal cardiomyocytes, examining overexpression and knockdown impacts on calcium transients and apoptosis.
- In vivo studies utilized ultrasound-targeted microbubble destruction to deliver human S100A6 plasmid to rat myocardium prior to induced ischemia-reperfusion.
- Control groups received either an empty plasmid or no therapy.
Main Results:
- S100A6 overexpression in vitro improved calcium handling and protected cardiomyocytes against hypoxia-reoxygenation-induced apoptosis.
- In vivo, S100A6 gene therapy significantly improved survival rates compared to control groups.
- S100A6 treatment reduced infarct size, enhanced left ventricular systolic function, and attenuated cardiac hypertrophy and fibrosis.
Conclusions:
- S100A6 gene therapy, delivered via ultrasound-targeted microbubble destruction, effectively ameliorates myocardial ischemia-reperfusion injury.
- This approach leads to reduced mortality, improved cardiac function, and decreased pathological remodeling post-ischemia-reperfusion.
- S100A6 represents a promising therapeutic target for managing acute myocardial infarction.
Background:
Cardiomyocyte-specific transgenic mice overexpressing S100A6, a member of the family of EF-hand calcium-binding proteins, develop less cardiac hypertrophy, interstitial fibrosis, and myocyte apoptosis after permanent coronary ligation, findings that support S100A6 as a potential therapeutic target after acute myocardial infarction. Our purpose was to investigate S100A6 gene therapy for acute myocardial ischemia-reperfusion.
Methods And Results:
We first performed in vitro studies to examine the effects of S100A6 overexpression and knockdown in rat neonatal cardiomyocytes. S100A6 overexpression improved calcium transients and protected against apoptosis induced by hypoxia-reoxygenation via enhanced calcineurin activity, whereas knockdown of S100A6 had detrimental effects. For in vivo studies, human S100A6 plasmid or empty plasmid was delivered to the left ventricular myocardium by ultrasound-targeted microbubble destruction in Fischer-344 rats 2 days prior to a 30-minute ligation of the left anterior descending coronary artery followed by reperfusion. Control animals received no therapy. Pretreatment with S100A6 gene therapy yielded a survival advantage compared to empty-plasmid and nontreated controls. S100A6-pretreated animals had reduced infarct size and improved left ventricular systolic function, with less myocyte apoptosis, attenuated cardiac hypertrophy, and less cardiac fibrosis.
Conclusions:
S100A6 overexpression by ultrasound-targeted microbubble destruction helps ameliorate myocardial ischemia-reperfusion, resulting in lower mortality and improved left ventricular systolic function post-ischemia-reperfusion via attenuation of apoptosis, reduction in cardiac hypertrophy, and reduced infarct size. Our results indicate that S100A6 is a potential therapeutic target for acute myocardial infarction.
