AimsImpaired myocardial sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) activity is a
hallmark of failing hearts, and SERCA2a gene therapy improves cardiac function in
animals and patients with heart failure (HF). Deregulation of microRNAs has been
demonstrated in HF pathophysiology. We studied the effects of therapeutic AAV9.SERCA2a
gene therapy on cardiac miRNome expression and focused on regulation, expression, and
function of miR-1 in reverse remodelled failing hearts.Methods and resultsWe studied a chronic post-myocardial infarction HF model treated with AAV9.SERCA2a gene
therapy. Heart failure resulted in a strong deregulation of the cardiac miRNome. miR-1
expression was decreased in failing hearts, but normalized in reverse remodelled hearts
after AAV9.SERCA2a gene delivery. Increased Akt activation in cultured cardiomyocytes
led to phosphorylation of FoxO3A and subsequent exclusion from the nucleus, resulting in
miR-1 gene silencing. In vitro SERCA2a expression also rescued miR-1 in
failing cardiomyocytes, whereas SERCA2a inhibition reduced miR-1 levels. In
vivo, Akt and FoxO3A were highly phosphorylated in failing hearts, but
reversed to normal by AAV9.SERCA2a, leading to cardiac miR-1 restoration. Likewise,
enhanced sodium–calcium exchanger 1 (NCX1) expression during HF was normalized by
SERCA2a gene therapy. Validation experiments identified NCX1 as a novel functional miR-1
target.ConclusionSERCA2a gene therapy of failing hearts restores miR-1 expression by an
Akt/FoxO3A-dependent pathway, which is associated with normalized NCX1 expression and
improved cardiac function.
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