Moreover, while these authors suggest that DDB1-Cul4A-ROC1 ligase is the physiological ligase impaired in cardiac hypertrophy, heart failure or hypertension, conditions linked to adrenergic overdrive and excessive PKA activation, others have demonstrated that defective cardiac Mdm2 led to a significant increase in GRK2, resulting in severely impaired cardiac function [102]. The gene discussed is GRK2; the disease is heart failure.