SERCA2a gene therapy restores microRNA-1 expression in heart failure via an Akt/FoxO3A-dependent pathway

Abstract

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.

MicroRNAs in myocardial ischemia: identifying new targets and tools for treating heart disease. New frontiers for miR-medicine

“…Myocardial sarcoplasmic reticulum Ca 2+ ATPase 2a (SeRCA2a) is downregulated in heart failure and SeRCA2a gene therapy improves cardiac function in both animals and patients [108]. Intriguingly, miR-1 is downregulated in heart failure and SeRCA2a gene therapy is able to restore miR-1 expression in heart failure via an Akt/Foxo3a-dependent pathway [109]. Notably, in the adult heart, both miR-1 and miR-133, which are in the same bicistronic unit, display an anti-hypertrophic activity [110,111].…”

Ketanserin improves cardiac performance after myocardial infarction in spontaneously hypertensive rats partially through restoration of baroreflex function

“…During the sham operation for MI, the silk suture around the left anterior descending coronary artery was not ligated. The mortality after the coronary artery ligature was approximately 50% and typically occurred within 1 week of surgery [22] .…”

MicroRNAs Are Involved in End-Organ Damage During Hypertension

“…31 MiR-1-1 and miR-1-2, representing 40% of all expressed cardiac miRs, derepress certain elements of the cytoskeleton, such as twinfilin-1, to provoke cardiac hypertrophy. 32 MiR-1 negatively regulates expression of several hypertrophy-associated genes, such as calmodulin and myocyte enhancer factor 2a, 33 sarco/endoplasmic reticulum calcium-dependent ATPase 2a, 34 and insulin growth factor 1. 35,36 MiR-133 itself is downregulated in cardiac hypertrophy.…”