Background:
Atrial fibrillation (AF) increases stroke risk five-fold. Atrial hypocontractility from atrial myosin light chain (MLC2a) dephosphorylation contributes to stroke risk in AF. Recent proteomic data has shown increased protein phosphatase 1 subunit 12C (PPP1R12C) targeting to MLC2a in AF. However, it is unclear whether PPP1R12C causes MLC2a dephosphorylation in AF.
Objective:
Determine whether increased PPP1R12C expression causes MLC2a dephosphorylation and increases AF risk.
Methods:
Western blots and co-IPs were performed to evaluate the relationship among PPP1R12C, PP1c and MLC2a in human atrial tissues (AF vs SR). Mice with either a knockout (KO) or lentiviral (LV) cardiac overexpression of PPP1R12C were evaluated with invasive EP studies for AF inducibility vs WT controls.
Results:
In human AF, PPP1R12C was increased 4-fold (
P
<0.005, n=6) with an 88% reduction in S-19-MLC2a phosphorylation (
P
<0.05, n=4). PPP1R12C-PP1c and PPP1R12C-MLC2a binding was increased 2-fold in AF (
P
<0.05, n=6). AF burden in LV-12C mice increased nearly tenfold vs. KO and WT mice (
P
<0.05, n=6).
Conclusion:
In human AF, increased PPP1R12C expression is associated with reduced P-MLC2a through enhanced binding with the PP1c catalytic subunit. This dephosphorylation is a likely contributor to atrial hypocontractility and stroke risk in AF. Additionally, increased PPP1R12C expression in mice increases AF risk. Future studies will examine the effects of increased PPP1R12C expression upon atrial contractile function in mice.
Chamber specification of atrial myosin light chain-2 expression precedes septation during murine cardiogenesis