The N-end rule pathway is a proteolytic system in which destabilizing N-terminal 
amino acids of short lived proteins are recognized by recognition components 
(N-recognins) as an essential element of degrons, called N-degrons. In 
eukaryotes, the major way to generate N-degrons is through arginylation by ATE1 
arginyl-tRNA-protein transferases, which transfer Arg from aminoacyl-tRNA to 
N-terminal Asp and Glu (and Cys as well in mammals). We have shown previously 
that ATE1-deficient mice die during embryogenesis with defects in cardiac and 
vascular development. Here, we characterized the arginylation-dependent N-end 
rule pathway in cardiomyocytes. Our results suggest that the cardiac and 
vascular defects in ATE1-deficient embryos are independent from each other and 
cell-autonomous. ATE1-deficient myocardium and cardiomyocytes therein, but not 
non-cardiomyocytes, showed reduced DNA synthesis and mitotic activity ~24 h 
before the onset of cardiac and vascular defects at embryonic day 12.5 
associated with the impairment in the phospholipase C/PKC-MEK1-ERK axis of 
Gα(q)-mediated cardiac signaling pathways. Cardiac overexpression of Gα(q) 
rescued ATE1-deficient embryos from thin myocardium and ventricular septal 
defect but not from vascular defects, genetically dissecting vascular defects 
from cardiac defects. The misregulation in cardiovascular signaling can be 
attributed in part to the failure in hypoxia-sensitive degradation of RGS4, a 
GTPase-activating protein for Gα(q). This study is the first to characterize the 
N-end rule pathway in cardiomyocytes and reveals the role of its arginylation 
branch in Gα(q)-mediated signaling of cardiomyocytes in part through 
N-degron-based, oxygen-sensitive proteolysis of G-protein regulators.