Silencing of miR-34a Attenuates Cardiac Dysfunction in a Setting of Moderate, but Not Severe, Hypertrophic Cardiomyopathy

Abstract

Therapeutic inhibition of the miR-34 family (miR-34a,-b,-c), or miR-34a alone, have emerged as promising strategies for the treatment of cardiac pathology. However, before advancing these approaches further for potential entry into the clinic, a more comprehensive assessment of the therapeutic potential of inhibiting miR-34a is required for two key reasons. First, miR-34a has ∼40% fewer predicted targets than the miR-34 family. Hence, in cardiac stress settings in which inhibition of miR-34a provides adequate protection, this approach is likely to result in less potential off-target effects. Secondly, silencing of miR-34a alone may be insufficient in settings of established cardiac pathology. We recently demonstrated that inhibition of the miR-34 family, but not miR-34a alone, provided benefit in a chronic model of myocardial infarction. Inhibition of miR-34 also attenuated cardiac remodeling and improved heart function following pressure overload, however, silencing of miR-34a alone was not examined. The aim of this study was to assess whether inhibition of miR-34a could attenuate cardiac remodeling in a mouse model with pre-existing pathological hypertrophy. Mice were subjected to pressure overload via constriction of the transverse aorta for four weeks and echocardiography was performed to confirm left ventricular hypertrophy and systolic dysfunction. After four weeks of pressure overload (before treatment), two distinct groups of animals became apparent: (1) mice with moderate pathology (fractional shortening decreased ∼20%) and (2) mice with severe pathology (fractional shortening decreased ∼37%). Mice were administered locked nucleic acid (LNA)-antimiR-34a or LNA-control with an eight week follow-up. Inhibition of miR-34a in mice with moderate cardiac pathology attenuated atrial enlargement and maintained cardiac function, but had no significant effect on fetal gene expression or cardiac fibrosis. Inhibition of miR-34a in mice with severe pathology provided no therapeutic benefit. Thus, therapies that inhibit miR-34a alone may have limited potential in settings of established cardiac pathology.

MicroRNA-34a Plays a Key Role in Cardiac Repair and Regeneration Following Myocardial Infarction

“…In settings of established cardiac injury, it is likely that antagonism of miR-34a alone is insufficient to promote cardiac regeneration, and a more broad inhibition of miR-34 family members is required. 19, 33 …”

From Bench to Bedside: New Approaches to Therapeutic Discovery for Heart Failure

“…Whilst most investigators examine the potential of inhibiting miRNAs that have increased expression in a cardiac disease setting (see review [55]), Bernardo and colleagues therapeutically target miRNAs that display differential expression in settings of cardiac stress and protection [64–67]. Inhibition of miR-34, miR-34a, or miR-652 with miRNA inhibitors was associated with reduced pathology and improved cardiac function in mouse models of cardiac disease via mechanisms that are associated with preserved angiogenesis, decreased fibrosis and a more favourable cardiac molecular profile (e.g.…”

“…Inhibition of miR-34, miR-34a, or miR-652 with miRNA inhibitors was associated with reduced pathology and improved cardiac function in mouse models of cardiac disease via mechanisms that are associated with preserved angiogenesis, decreased fibrosis and a more favourable cardiac molecular profile (e.g. attenuation of ANP, BNP gene expression) [64–66]. Further, treatment with these miRNA inhibitors was associated with upregulation of target genes implicated in angiogenesis, contractile function and cell survival [65, 66].…”

Therapeutic potential of targeting microRNAs to regulate cardiac fibrosis: miR-433 a new fibrotic player

“…Each of these miRNAs, or their family members, have previously been shown to be elevated in hearts of cardiac stress mouse models associated with fibrosis (e.g., MI, pressure overload, dilated cardiomyopathy and atrial fibrillation), and targeting these miRNAs was effective in preventing or attenuating fibrosis in vivo (5,(7)(8)(9)(10)(11)(12)(13)(14). Other studies have identified numerous additional miRNAs dysregulated in cardiac fibrotic models.…”