miR-208a as a Biomarker of Isoproterenol-induced Cardiac Injury in Sod2^+/− and C57BL/6J Wild-type Mice

Abstract

This investigation examined microRNA-208a (miR-208a) as a potential biomarker of isoproterenol (ISO)-induced cardiac injury in superoxide dismutase-2 (Sod2(+/-) ) and the wild-type mice, and the potential sensitivity of Sod2(+/-) mice to ISO-induced toxicity. A single intraperitoneal injection of ISO was administered to age-matched wild-type and Sod2(+/-) mice at 0, 80, or 160 mg/kg. Plasma miR-208a, cardiac troponin I (cTnI), and ISO systemic exposure were measured at various time points postdose. Hearts were collected for histopathology examination and for tissue expression of miR-208a and myosin heavy chain 7. ISO administration caused increases in cTnI and miR-208a plasma levels that correlated with myocardial damage; however, the magnitude of increase differed according to the types of mice. At similar ISO systemic exposure, the magnitude of cTnI was greater in wild-type mice compared to Sod2(+/) (-) mice; however, the magnitude of miR-208a was greater in Sod2(+/-) mice than that of the wild-type mice. Myocardial degeneration occurred at ≥3 hr in the wild-type and ≥6 hr in Sod2(+/) (-) mice. At ≥24 hr after ISO administration, miR-208a appeared superior to cTnI in indicating myocardial injury in both wild-type and Sod2(+/-) mice. Sod2(+/-) mice were not more sensitive than wild-type mice to ISO-induced toxicity.

Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients

“…Interestingly, miR-208a (heart-specific miRNA) [17] and -208b were undetected in this study, although previously published studies have suggested them as new biomarkers of myocardial injury following myocardial infarction [18, 19] or isoproterenol use [5, 20, 21]. This discrepancy may be a result of a differential response of the cardiomyocytes to DOX stimuli.…”

MicroRNAs in injury and repair

“…Specifically, overexpression of miR-208a resulted in increased α-MHC expression and was associated with arrhythmias, fibrosis and hypertrophy in mice[72]. Following isoproteronol-induced cardiac injury in rats, miR-208a was shown to have stable upregulation in plasma and was superior to cardiac troponins in indicating injury[73, 74]. MiR-208a was also increased in the human heart tissue of patients who died from MI[75].…”

Micrornas as Pharmacogenomic Biomarkers for Drug Efficacy and Drug Safety Assessment

“…However, the potential for a new drug to cause cardiotoxicity may not be detected until after clinical trials in humans have begun. In some cases, drug-associated cardiotoxicity may not be observed until after drug approval [159,160]. The potential adverse effects of cardiotoxicity are arrhythmias, hypertension, abnormal left ventricular ejection fraction (LVEF) and eventually heart failure [161].…”

“…In addition, miR-208 increased with a similar time course with the plasma cTnI level. Another study by Liu et al [160] compared the role of miR-208a in isoprenaline-treated wild-type C57BL/6J mice and C57BL/6J mice that were heterozygous for Sod2 (Sod2 +/- ). They concluded that increases in miR-208a detected in plasma correlated more closely with isoprenaline-induced myocardial damage than cTnI levels in plasma in both types of mice.…”