Jason H. Karnes, Changlei Bao, Shuxin Liang, Timothy Thayer, John Zagorski, Samisubbu R. Naidu, James D. West, Rae-Hwi Schwantes-An, Ehsan Khajouei, Kasturi Banerjee, Hemant K. Tiwari, Juvie Farol, Kiana L. Martinez, Dingyuan Liu, Yao Ning, Yanan Sun, Yangfan Jia, Jian Wang, Amit Arora, Ken Batai, Stephen J. 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
University of Arizona. National Clinical Research Center for Respiratory Disease and First Affiliated Hospital of Guangzhou Medical University. Northwest A&F University. College of Veterinary Medicine. Vanderbilt University Medical Center. Indiana University. University of Alabama. Roswell Park Comprehensive Cancer Center. Buffalo. University of Wisconsin-Madison. Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine. Washington University School of Medicine. University of Florida. Ichan School of Medicine. Gansu Provincial Hospital.
China and United States
Circulation Research
Circ Res 2026;
DOI: 10.1161/CIRCRESAHA.125.327117
Abstract
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: Rs8057488 in the sorting nexin 29 (SNX29) gene reached genome-wide significance in the discovery cohort (P=4.00×10-8) and was nominally replicated (P=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.
Category
Class I. Pulmonary hypertension Associated with a Favorable Response to Nitric Oxide and Calcium Channel Blockers
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
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