| Autor: |
Bernardo BC; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia., Gao XM; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia., Tham YK; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia., Kiriazis H; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia., Winbanks CE; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia., Ooi JY; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia., Boey EJ; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia., Obad S; Santaris Pharma, Horsholm, Denmark., Kauppinen S; Department of Haematology, Aalborg University Hospital, Copenhagen, Denmark., Gregorevic P; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia., Du XJ; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia., Lin RC; Ramaciotti Centre for Genomics, School of Biotechnology & Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia., McMullen JR; Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia ; Departments of Medicine Monash University, Clayton, Victoria, Australia ; Departments of Physiology, Monash University, Clayton, Victoria, Australia. |
| Abstrakt: |
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. |
