Abstract 112: An Exercise-induced MicroRNA Pathway That Protects Against Apoptosis and Pathological Cardiac Dysfunction
Background: Exercise induces physiological cardiac growth and protects against adverse cardiac remodeling. microRNAs (miRNA) are important regulators in cardiovascular pathology and disease. Less is known about miRNA roles in the cardiac effects of exercise, and we investigated their roles in exercise-induced cardiac growth.
Methods and Results: Based on cardiac miRNA profiling in two exercise models (swimming, running) and functional screening in neonatal rat cardiomyocytes (NRCMs), miR-222 was selected for further study. miR-222 was upregulated ~2-fold in both exercise models, pathological hypertrophic and failing hearts (p<0.05). We found that ERK, JNK and p38 signal pathways are involved in FBS increasing miR-222 in NRCMs. miR-222 increased NRCM proliferation and size (p<0.01) and reduced NRCM apoptosis induced by serum starvation with or without doxorubicin. Four potential miR-222 targets (p27, Hipk1, Hipk2, and Hmbox-1) were identified and confirmed as direct targets. siRNA knockdown (KD) of p27 or Hipk2 inhibited NRCM apoptosis.
To investigate miR-222’s cardiac role in vivo, we made transgenic mice with cardiac-specific, inducible (TgI-miR-222) or constitutive (TgC-miR-222) expression of miR-222. RT-PCR showed that miR-222 is increased ~6-fold in TgI-miR-222 hearts after induction and ~10-fold in TgC-miR-222 hearts. Surprisingly, both transgenic lines have normal heart size and function, and the 4 miR-222 targets are unaffected at baseline. After ischemia-reperfusion injury (IRI), TgI-miR-222 had no difference in initial infarct size or dysfunction but were protected against adverse remodeling over the next six weeks with better function (p<0.01), less cardiac fibrosis (68%, p<0.05), and reduced CM apoptosis (300%, p<0.05). Two weeks after TAC, TgC-miR-222 had less increase in cardiac mass (HW/TL, p<0.05), better cardiac function ([[Unable to Display Character: ∆]]32%, p<0.01), reduced expression of markers of fibrosis (Col1a1, Col3a1, Mmp2, p<0.05) and apoptosis (Caspase 1, 3, 8, p<0.05). Four months after TAC, TgC-miR-222 had improved survival (p<0.05) compared to wide type controls.
Conclusion: Cardiac miR-222 is upregulated by exercise and protects against adverse remodeling and cardiac dysfunction after IRI or TAC.
Author Disclosures: X. Liu: None. J. Xiao: None. X. Wei: None. C. Platt: None. C. Xiao: None. F. Damilano: None. V. Bezzerides: None. A. Rosenzweig: None.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).
- © 2015 by American Heart Association, Inc.