MicroRNA-150 (miR-150) is downregulated in patients with multiple cardiovascular diseases and in diverse mouse models of heart failure (HF). miR-150 is significantly associated with HF severity and outcome in humans. We previously reported that miR-150 is activated by β-blocker carvedilol (Carv) and plays a protective role in the heart using a systemic miR-150 KO mouse model. However, mechanisms that regulate cell-specific miR-150 expression and function in HF are unknown. Here, we demonstrate that potentially novel conditional cardiomyocyte–specific (CM-specific) miR-150 KO (miR-150 cKO) in mice worsens maladaptive cardiac remodeling after myocardial infarction (MI). Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline–rich protein 1a (
Sprr1a
) as a potentially novel target of miR-150. Our studies further reveal that
Sprr1a
expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion, while its expression is downregulated in hearts and CMs by Carv. We also show that left ventricular
SPRR1A
is upregulated in patients with HF and that
Sprr1a
knockdown in mice prevents maladaptive post-MI remodeling. Lastly, protective roles of CM miR-150 are, in part, attributed to the direct and functional repression of proapoptotic
Sprr1a
. Our findings suggest a crucial role for the miR-150/SPRR1A axis in regulating CM function post-MI.
Background
The transmural distribution of apamin-sensitive small conductance Ca2+-activated K+ (SK) current (IKAS) in failing human ventricles remains unclear.
Methods and Results
We optically mapped left ventricular wedge preparations from 12 failing native hearts and 2 rejected cardiac allografts explanted during transplant surgery. We determined transmural action potential duration (APD) before and after 100 nM apamin administration in all wedges and after sequential administration of apamin, chromanol and E4031 in 4 wedges. Apamin prolonged APD from 363 ms [95% confidence interval (CI), 341 to 385] to 409 [CI, 385 to 434] (p<0.001) in all hearts, and reduced the transmural conduction velocity from 36 cm/s [CI, 30 to 42] to 32 cm/s [CI, 27 to 37] (p=0.001) in 12 native failing hearts at 1000 ms pacing cycle length (PCL). The percent APD prolongation is negatively correlated with baseline APD and positively correlated with PCL. Only one wedge had M-cell islands. The percentages of APD prolongation in the last 4 hearts at 2000 ms PCL after apamin, chromanol and E4031 were 9.1% [CI, 3.9 to 14.2], 17.3% [CI, 3.1 to 31.5] and 35.9% [CI, 15.7 to 56.1], respectively. Immunohistochemical staining of subtype 2 of SK (SK2) protein showed increased expression in intercalated discs of myocytes.
Conclusions
SK current is important in the transmural repolarization in failing human ventricles. The magnitude of IKAS is positively correlated with the PCL, but negatively correlated with APD when PCL is fixed. There is abundant SK2 protein in the intercalated discs of myocytes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.