Abstract
miRs (microRNAs, miRNAs) intricately regulate physiological and pathological processes. Although miR-7a/b protects against cardiomyocyte injury in ischemia/reperfusion injury, the function of miR-7a/b in myocardial infarction (MI)-induced cardiac remodeling remains unclear. Here, we sought to investigate the function of miR-7a/b in post-MI remodeling in a mouse model and to determine the underlying mechanisms involved. miR-7a/b overexpression improved cardiac function, attenuated cardiac remodeling and reduced fibrosis and apoptosis, whereas miR-7a/b silencing caused the opposite effects. Furthermore, miR-7a/b overexpression suppressed specific protein 1 (Sp1) and poly (ADP-ribose) polymerase (PARP-1) expression both in vivo and in vitro, and a luciferase reporter activity assay showed that miR-7a/b could directly bind to Sp1. Mithramycin, an inhibitor of the DNA binding activity of Sp1, effectively repressed PARP-1 and caspase-3, whereas knocking down miR-7a/b partially counteracted these beneficial effects. Additionally, an immunoprecipitation assay indicated that hypoxia triggered activation of the binding activity of Sp1 to the promoters of PARP-1 and caspase-3, which is abrogated by miR-7a/b. In summary, these findings identified miR-7a/b as protectors of cardiac remodeling and hypoxia-induced injury in H9c2 cardiomyoblasts involving Sp1 and PARP-1.
Highlights
Cardiovascular diseases are the most common cause of death worldwide; an estimated 620,000 Americans have had a new coronary attack, which is defined as the first hospitalized myocardial infarction (MI), or have died from coronary heart disease[1]
MiRs have been suggested as candidates in the treatment of MI-induced cardiac remodeling that may result in heart failure. miR-7 is an evolutionarily conserved mRNA in mammals, and miR-7a/b are the two subtype of miR-7, which differs by a single nucleotide in the mice6. miR-7a/b is an evolutionarily conserved mRNA in mammals, and functions in growth[7], migration and metastasis in tumor cells[8] and fibrosis in fibroblasts[9]
Results miR-7a/b overexpression improved cardiac function. miR-7a/b expression was quantified in the border zone of the myocardium post MI and compared to that in sham-operated mice
Summary
Cardiovascular diseases are the most common cause of death worldwide; an estimated 620,000 Americans have had a new coronary attack, which is defined as the first hospitalized myocardial infarction (MI), or have died from coronary heart disease[1]. During MI, maintaining efficient cardiomyocytes as best as possible is critical for the preservation of cardiac structural integrity and function because oxidative stress, along with insufficient oxygen and blood supply to the heart, leads to the irreparable loss of cardiomyocytes, and this damage is exacerbated by the toxic substances released from dead cells[2,3]. In addition to these immediate biological reactions, the dead cells and toxic substances trigger left ventricular remodeling, which eventually leads to functional decomposition and heart failure (HF)[4]. We focused on the regulation of Sp1 by miR-7a/b, with the goal of identifying potential new therapies for ischemic heart failure
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