Jason H. Karnes, Changlei Bao, Shuxin Liang, Timothy Thayer, John Zagorski, Samisubbu R. Naidu, James D. West, Tae-Hwi Schwantes-An, Ehsan Khajouei, Kasturi Banerjee, Hemant K. Tiwari, Juvie Farol, Kiana L. Martinez, D Q Liu, Ning Yao, Yanan Sun, Yangfan Jia, Jian Wang, Amit Arora, Ken Batai, Stephen Halliday, Katie Lutz, Anna Walsworth, Andrea L. Frump, Olga Rafikova, Zhiyu Dai, Joe G.N. Garcia, Il‐man Kim, Anna R Hemnes, Evan Brittain, Raymond L. Benza, William C. Nichols, Aiai Chu, Haiyang Tang, Ankit A. Desai
BACKGROUND: Although pulmonary arterial hypertension (PAH) is a rare and fatal disease that is well-characterized, vasodilator-responsive PAH accounts for a minority of cases, with little mechanistic knowledge, but with dramatically improved survival. METHODS: By assembling national cohorts, we evaluated genetic influences on acute vasodilator drug response, a key determinant of the presence of vasodilator-responsive PAH. Differences between hemodynamics at rest and after a PAH-specific vasodilator were tested in a genome-wide association study. Validated loci were functionally tested in cell culture and in a hypoxic mouse model of pulmonary hypertension. RESULTS: =0.027). Consistent with its predicted function, SNX29 demonstrated an endosomal distribution in PA smooth muscle cells. Silencing SNX29 redistributed stromal interaction molecule proteins to the cell membrane and enhanced store-operated calcium entry. Over-expression of SNX29, in vivo, attenuated hypoxic vasoconstriction in isolated perfused murine lung models. CONCLUSIONS: The data cumulatively suggest SNX29 may contribute to vasodilation partly through reduced store-operated calcium entry and endosomal trafficking of store-operated calcium entry proteins, advancing our understanding of vasodilator-responsive PAH.