What is the clinical evidence from this study?

Study design: Other. Population: Myocardial Infarction / Heart Failure. Intervention: Sprr1a knockdown (Sprr1ahypo/hypo) vs. miR-150 KO mice and WT mice. Primary outcome: Cardiac function and remodeling post-MI.

What does this research mean for the field?

The cardioprotective effects of miR-150 during post-myocardial infarction remodeling and human cardiac fibroblast activation are directly mediated by its functional repression of the profibrotic protein SPRR1A. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

July 19, 2023Open Access

SPRR1A is a key downstream effector of MiR-150 during both maladaptive cardiac remodeling in mice and human cardiac fibroblast activation

Key Result

Sprr1a knockdown in miR-150 knockout mice significantly attenuated adverse post-myocardial infarction remodeling, including cardiac dysfunction, fibrosis, and apoptosis.

Structured PICO

Population

miR-150 knockout; Sprr1a-hypomorphic (Sprr1a hypo/hypo) mouse model and human cardiac fibroblasts (HCFs)

Intervention

Sprr1a knockdown and carvedilol exposure

Outcome

Post-MI remodeling effects and cardiac fibroblast activationsurrogate

The study delineates a pivotal functional interaction between miR-150 and SPRR1A as a novel regulatory mechanism pertinent to cardiac fibroblast activation and ischemic heart failure.

Limitations

Systemic knockdown of Sprr1a was used, so expression in other myocardial cells may play a role.
Additional immunohistochemical assessments and gene expression studies during AMI are needed.
miR-150 may also have other targets mediating distinct functions.
Downstream targets and mechanisms of SPRR1A that regulate CF activation remain elusive.
Additional methods like the Simpson method and pressure-volume loop analysis are required to measure cardiac function more accurately.
The mode of action in mice could be different in human cells.
Other in vivo injury models are warranted.

Abstract

Abstract MicroRNA-150 (miR-150) is conserved between rodents and humans, is significantly downregulated during heart failure (HF), and correlates with patient outcomes. We previously reported that miR-150 is protective during myocardial infarction (MI) in part by decreasing cardiomyocyte (CM) apoptosis and that proapoptotic small proline-rich protein 1a ( Sprr1a ) is a direct CM target of miR-150. We also showed that Sprr1a knockdown in mice improves cardiac dysfunction and fibrosis post-MI and that Sprr1a is upregulated in pathological mouse cardiac fibroblasts (CFs) from ischemic myocardium. However, the direct functional relationship between miR-150 and SPRR1A during both post-MI remodeling in mice and human CF (HCF) activation was not established. Here, using a novel miR-150 knockout; Sprr1a -hypomorphic ( Sprr1a hypo/hypo ) mouse model, we demonstrate that Sprr1a knockdown blunts adverse post-MI effects caused by miR-150 loss. Moreover, HCF studies reveal that SPRR1A is upregulated in hypoxia/reoxygenation-treated HCFs and is downregulated in HCFs exposed to the cardioprotective β-blocker carvedilol, which is inversely associated with miR-150 expression. Significantly, we show that the protective roles of miR-150 in HCFs are directly mediated by functional repression of profibrotic SPRR1A . These findings delineate a pivotal functional interaction between miR-150 and SPRR1A as a novel regulatory mechanism pertinent to CF activation and ischemic HF.

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