MURC, a Muscle-Restricted Coiled-Coil Protein That Modulates the Rho/ROCK Pathway, Induces Cardiac Dysfunction and Conduction Disturbance

Abstract

We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

“…Approximately 42% of MURC Tg show cardiac arrhythmia up to 5 months of age 40 . Thus, for this study, mice were examined at 11-12 months of age; at this age all mice displayed arrhythmia.…”

“…Mice were housed in a 12-h light-dark cycle in a temperaturecontrolled environment. In this study, we used two models that develop HF over time and display an increased susceptibility to AF: (i) cardiac-specific dnPI3K-Mst1 Tg mice 20 referred to as HF þ AF model and (ii) cardiac-specific MURC Tg mice 40 .…”

“…In the MURC model at 3-4 months of age, cardiac morphology and function are less severe than that of the HF þ AF model (that is, dnPI3K-Mst1), and episodes of arrhythmia were only identified in approximately 42% of mice at this age 40 . Thus, a cohort of MURC mice and Ntg littermate controls were aged to 11-12 months before treatment with BGP-15 or saline for 4 weeks.…”

“…To assess the therapeutic potential of BGP-15 in an independent mouse model with HF and AF, BGP-15 was administered to cardiac-specific muscle-restricted coiled-coil (MURC) Tg mice, which develop DCM, HF and display atrial arrhythmias 40 . MURC activates the Ras homolog gene family, member A (RhoA)/Rho-associated, coiled-coil-containing protein kinase (ROCK) pathway, increases Anp and regulates myofiber organization.…”

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

“…These include gene disruption/mutation of connexin40, KCNE1, or nuclear core component NUP155, [5][6][7] overexpression of RhoA, 8 basic leucine zipper inhibitor protein: JDP2, 9 angiotensin converting enzyme, 10 tumor necrosis factor ␣, 11 Rac1, 12 and MURC. 13 AF often occurs in combination with heart failure, although the factors that precipitate the onset of AF in patients with (or without) pre-existing heart disease remain unclear.…”