Abstract
Using in vitro, in vivo and patient-based approaches, we investigated the potential of circulating microRNAs (miRNAs) as surrogate biomarkers of myocardial steatosis, a hallmark of diabetic cardiomyopathy. We analysed the cardiomyocyte-enriched miRNA signature in serum from patients with well-controlled type 2 diabetes and with verified absence of structural heart disease or inducible ischemia, and control volunteers of the same age range and BMI (N = 86), in serum from a high-fat diet-fed murine model, and in exosomes from lipid-loaded HL-1 cardiomyocytes. Circulating miR-1 and miR-133a levels were robustly associated with myocardial steatosis in type 2 diabetes patients, independently of confounding factors in both linear and logistic regression analyses (P < 0.050 for all models). Similar to myocardial steatosis, miR-133a levels were increased in type 2 diabetes patients as compared with healthy subjects (P < 0.050). Circulating miR-1 and miR-133a levels were significantly elevated in high-fat diet-fed mice (P < 0.050), which showed higher myocardial steatosis, as compared with control animals. miR-1 and miR-133a levels were higher in exosomes released from lipid-loaded HL-1 cardiomyocytes (P < 0.050). Circulating miR-1 and miR-133a are independent predictors of myocardial steatosis. Our results highlight the value of circulating miRNAs as diagnostic tools for subclinical diabetic cardiomyopathy.
Highlights
The identification of blood biomarkers of myocardial steatosis could permit routine population-wide screening, allowing early diagnosis and anticipation of cardiac dysfunction
We explored the potential of cardiomyocyte-enriched miRNAs as surrogate biomarkers of myocardial steatosis in patients with well-controlled type 2 diabetes of short duration and with verified absence of cardiac structural heart disease or inducible ischemia, and in a high-fat diet-fed murine model of insulin resistance
Quantitative PCR assessment revealed that expression levels of serum miR-1 and miR-133a were directly associated with myocardial steatosis, independently of potential confounding factors
Summary
The identification of blood biomarkers of myocardial steatosis could permit routine population-wide screening, allowing early diagnosis and anticipation of cardiac dysfunction. Clinical studies have proposed peripheral blood microRNAs (miRNAs) as sensitive, specific and non-invasive biomarkers for the early monitoring of alterations in cardiac viability, structure, and function[13, 14]. Distinctive circulating miRNA signatures with clinical value have been described in coronary heart disease[15], acute coronary syndrome[16], heart failure[17], various cardiomyopathies[18, 19], and type 2 diabetes and its related vascular complications[20,21,22,23,24,25]. We hypothesized that circulating miRNAs could be used to monitor myocardial neutral lipid content in type 2 diabetes. We explored the potential of cardiomyocyte-enriched miRNAs as surrogate biomarkers of myocardial steatosis in patients with well-controlled type 2 diabetes of short duration and with verified absence of cardiac structural heart disease or inducible ischemia, and in a high-fat diet-fed murine model of insulin resistance. The results obtained from patients and both in vivo and in vitro models suggest that serum miR-1 and miR-133a levels hold significant promise as clinical indicators of myocardial steatosis
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