Decreased Expression of miR-133a but Not of miR-1 is Associated with Signs of Heart Failure in Patients Undergoing Coronary Bypass Surgery

Abstract

Objectives: Coronary artery disease (CAD)-associated ischemic heart failure is characterized by dysregulated gene expression which is partly mediated by microRNAs (miRNAs). While the muscle-specific miR-1 and miR-133 are involved in cardiac development and hypertrophy, their role in heart failure resulting from CAD is unknown. We, therefore, tested the hypothesis that cardiac miR-1 and miR-133 expression is associated with signs of heart failure in patients undergoing coronary artery bypass grafting. Methods: 83 patients were included in this prospective study. Cardiac index and vascular pressures were measured under general anesthesia and the miRNA expression was quantified (RNase protection assay and real-time PCR) from samples of the right atrial myocardium. Results: miR-133 expression decreased significantly with increased severity of heart failure, as indicated by a greater New York Heart Association (NYHA) functional class (p = 0.014) and increased pulmonary artery occlusion pressure (p = 0.045). Furthermore, patients with NT-proBNP concentrations >1,800 pg/ml showed a 25% decrease in miR-133 expression compared to patients with concentrations <300 pg/ml (p = 0.023). In contrast, no associations were detected for miR-1 expression. Conclusions: In surgical CAD patients, a decreased miR-133 expression is associated with variables characteristic of heart failure. This supports a role for miR-133 but not miR-1 in the adaption to and/or remodeling of the ischemic heart.

Biventricular Pacing Cardiac Contractility Modulation Improves Cardiac Contractile Function via Upregulating SERCA2 and miR-133 in a Rabbit Model of Congestive Heart Failure

“…miR-133 is a muscle-specific and cardiac-enriched miRNA, and its expression is found markedly repressed in heart failure in both animal models and human subjects [19,20,21,22]. Our results presented in Figure 5 confirmed downregulation of miR-133 in cardiac tissues.…”

“…On the other hand, downregulation of miR-133 in failing heart has also been consistently observed by several laboratories [20,21,22,27,28]. Though how this downregulation contributes to heart failure remains incompletely understood, it is known that miR-133 produces cardioprotective effects against myocardial injuries under various conditions via targeting genes related to cardiac contractile function and fibrosis [19,20,26,28,36,37,38,39,40,41], except for its potential arrhythmogenic effect [42].…”

“…Finally, our results show that at the molecular level, BVP-CCM upregulated SERCA2a and miR-133 to greater extends than single ventricular pacing. This property of BVP-CCM is expected to better improve intracellular Ca 2+ handling and cardiac contractile function given the fact that SERCA2a and miR-133 both are key determinants of Ca 2+ handling process in cardiac cells [10,11,12,19,27,28] and are both downregulated in failing heart [9,10,11,12,19,20,21,22]. SERCA2a is a critical ATPase responsible for Ca 2+ re-uptake during excitation-contraction coupling, and impaired Ca 2+ uptake consequent to decreased expression and activities of SERCA2a is a hallmark of heart failure characterized by severe contractile dysfunction both in vitro and in vivo .…”

“…Though how this downregulation contributes to heart failure remains incompletely understood, it is known that miR-133 produces cardioprotective effects against myocardial injuries under various conditions via targeting genes related to cardiac contractile function and fibrosis [19,20,26,28,36,37,38,39,40,41], except for its potential arrhythmogenic effect [42]. It is therefore likely that correction of miR-133 downregulation in failing heart should give rise to beneficial effects.…”

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…Patients with aortic stenosis surgery [194] Apelin treatment reduces elevated circulating miRs Elevated miR-133a, miR-208 and miR-1 reduced High-fat diet elevated miRs and increased left ventricular diastolic and systolic diameters, and wall thickness Obesity-associated cardiac dysfunction in mouse model [195] NAC treatment Expressed miR-1, miR-499, miR-133a, and miR-133b were strongly depressed in the diabetic cardiomyocytes NAC restored expression of miR-499, miR-1, miR-133a, and miR-133b significantly in the myocardium Diabetic rat hearts [196] Myocardial junctin elevated miR-1 targets junctin NAC reduces junction levels Development of diabetic cardiomyopathy in rat hearts [196] CAD associated ischemic heart failure miR-133 expression decreased with increased severity of heart failure Patients with CAD [197] Runx2 miR-133a targets Runx2 Transition of VSMCs to osteoblast-like cells [198] Increased alkaline phosphatase activity, osteocalcin secretion and Runx2 expression miR-133a was decreased during osteogenic differentiation…”