Background and Aims:
Cardiac injury induces dynamic changes in the expression of microRNAs (miRs). For example, the evolutionarily conserved miR-150 is downregulated in patients with multiple cardiovascular diseases such as myocardial infarction (MI) and cardiomyopathies, as well as in various mouse models of heart failure (HF). MiR-150 is significantly associated with HF severity and outcome in humans. Using a systemic miR-150 knockout (KO) mouse model, we previously showed that carvedilol (Carv)/β
1
-adrenergic receptor/β-arrestin1-responsive miR-150 confers cardiac protection against MI (Left side in Figure). However, the extent to which expression of miR-150 in cardiomyocytes (CMs) regulates MI is unknown and there is a lack of mechanistic insight by which CM miR-150 modulates cardiac protection.
Methods and Results:
Here, we demonstrate using a novel mouse model that conditional CM-specific miR-150 KO (miR-150 cKO) in mice worsens cardiac dysfunction, stress, fibrosis and apoptosis post-MI, without affecting mortality or inflammation. Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline-rich protein 1a (sprr1a) as a novel regulatory target of miR-150. Our mouse and CM studies further reveal that
sprr1a
expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion. In contrast, its expression is downregulated in hearts and CMs by Carv. Our human heart data also show that left ventricular
sprr1a
is upregulated in patients with HF with reduced ejection fraction. Mechanistically, the cardioprotective roles of CM miR-150 during MI are in part attributed to the direct and functional repression of pro-apoptotic gene
sprr1a
in CMs (Right side in Figure).
Conclusions:
These findings reveal a pivotal role for the miR-150/sprr1a axis in regulating CM function post-MI, and this novel axis could be a therapeutic target for intervention in ischemic heart disease.
Cardiomyocyte microRNA-150 confers cardiac protection and directly represses proapoptotic small proline–rich protein 1A
