Dissecting the Role of G-Protein–Coupled Receptor Kinase 2 for Excitation-Contraction Coupling

Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension

“…Among candidate molecules, the sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) is one that regulates intracellular Ca 2+ levels, and, thereby, pulmonary smooth muscle cell proliferation and vasoconstriction, and is known to be downregulated in remodeled pulmonary blood vessels isolated from patients with PAH as compared to patients with other forms of lung disease. 44 As activation of α-adrenergic signaling increases intracellular Ca 2+ levels in PAH, restoring SERCA2a expression and activity is one method to decrease intracellular Ca 2+ levels and modify pulmonary vascular remodeling (Figure 4). In monocrotaline-PAH rats with documented downregulation of SERCA2a in the pulmonary arterioles and RV, intratracheal aerosolized gene transfer of aerosolized adeno-associated virus serotype 1 (AAV1) carrying SERCA2a resulted in efficient transduction of the pulmonary vasculature leading to a reduction in pulmonary artery pressures, vascular remodeling, and RV hypertrophy.…”