No abstract

Pulmonary hypertension (PH) involves stress‐mediated pathways producing endothelial and smooth muscle cell dysfunction. The actin cytoskeleton is important in vascular remodeling and our earlier studies strongly suggested the role of caldesmon (Cald1) in endothelial cytoskeleton remodeling. Cald1 exhibits 2 isoforms: h‐Cald1 found in smooth muscle and l‐Cald1, expressed in non‐muscle cells and involved in cell proliferation and contractility. Both Cald1 isoforms are important in hypoxia‐induced PH and Cald1 surfaced as a candidate gene in 2 rodent PH therapy trials (simvastatin and sorafenib, Sor). We hypothesized that l‐Cald1 is an important regulator of vascular remodeling in PH. We validated Sor array data with increased l‐ and h‐ Cald1 protein levels in lung homgenates from hypoxia‐(1.5‐ & 2.5‐fold) and in hypoxia/SU5416 (H‐SU)‐ challenged rats (2‐ & 4‐fold compared to normoxia at 3.5 wks). Sor treatment reduced l‐ Cald1 levels in H‐SU while h‐ Cald1 remained elevated. Given isoform‐specific changes, we examined l‐Cald1 in vitro in HLMECs exposed to hypoxia (30 min‐4h). Gene and protein l‐Cald1 levels were increased at 1h (2.5‐ & 1.8‐fold) and 4h (1.6‐fold). Diphosphorylated myosin light chain (dpMLC) levels increased (2‐fold) by 30 min and decreased (1.5‐fold) by 2h with no change in total MLC. Thus, l‐Cald is potentially a key regulator in vascular remodeling in PH. NIH support: F32 HL090359‐01