Aquaporin 1 regulates pulmonary arterial smooth muscle cell apoptosis

Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by functional and structural vascular changes that lead to right heart failure and death. PAH pathogenesis involves remodeling of distal small diameter pulmonary arteries, including the development of vaso‐occlusive lesions featuring proliferation, migration and reduced apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Patients often present with late disease, where targeting apoptosis to reverse remodeling would be of benefit; unfortunately, no such therapy currently exists. Apoptosis is a complex process, often involving disruption of the mitochondrial membrane and release of cytochrome c to activate the downstream effector, caspase 3, the final executioner of apoptosis. Formerly, we showed that the water channel protein, aquaporin 1 (AQP1), is a key molecule mediating PASMC proliferation and migration by increasing β‐catenin levels. Others have shown in different cell types that activating β‐catenin prevent apoptosis and improved cell survival. Therefore, in this study, we explored whether AQP1 also regulates PASMC survival and/or susceptibility to apoptosis. Primary cultured rat distal PASMCs were isolated from the SU5416‐hypoxia (SuHx) rat model of PAH or control rats. PASMCs from SuHx rats exhibited lack of apoptosis, measured by: 1) visualizing nuclear morphology via Hoechst 33342 staining; 2) cleaved caspase 3 expressions; and 3) caspase 3 activity, both at baseline and in response to the apoptotic stimuli staurosporine (ST) or H2O2. AQP1 mRNA and protein expression were significantly elevated in PASMCs from SuHx rats. Not surprisingly, β‐catenin levels were also elevated in these cells. Compared to non‐targeting siRNA, depleting AQP1 induced apoptosis at baseline in both control and SuHx rat PASMCs. Furthermore, reduction of AQP1 sensitized SuHx PASMCs to apoptotic stimuli. Our results indicate that AQP1 is a critical regulator of apoptosis in PASMCs, controlling caspase 3 activation, potentially through a pathway involving β‐catenin. Moreover, these findings suggest the possibility that targeting AQP1 might provide an attractive therapeutic option to both stop the progression of, and even reverse, vascular remodeling in PAH.Support or Funding InformationHL126514This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.