Variation in <i>SNX29</i> and Acute Vasodilator Response in Pulmonary Arterial Hypertension

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.

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Publication Details

Journal
Circulation Research
Published
2026-05-18
DOI
https://doi.org/10.1161/circresaha.125.327117
Primary Topic
Pulmonary Hypertension Research and Treatments
Type
article
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article

Variation in SNX29 and Acute Vasodilator Response in Pulmonary Arterial Hypertension

Hemant K. Tiwari, Samisubbu R. Naidu, Kasturi Banerjee, Zhiyu Dai et al.
Circulation Research
Pulmonary Hypertension Research and Treatments
article

Variation in SNX29 and Acute Vasodilator Response in Pulmonary Arterial Hypertension

Hemant K. Tiwari, Samisubbu R. Naidu, Kasturi Banerjee, Zhiyu Dai, Ning Yao, Jason H. Karnes, Kiana L. Martinez, John Zagorski, D Q Liu, Yangfan Jia, Stephen Halliday, Ken Batai, Ehsan Khajouei, Il‐man Kim, Ankit A. Desai, Olga Rafikova, Juvie Farol, Katie Lutz, Yi-Xiang Wang, Evan Brittain, Tae-Hwi Schwantes-An, Anna Walsworth, Changlei Bao, Yanan Sun, William C. Nichols, Shuxin Liang, James D. West, Raymond L. Benza, Aiai Chu, Amit Arora, Anna R Hemnes, Haiyang Tang, Andrea L. Frump, Timothy Thayer, Joe G.N. Garcia
article en

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.

Circulation Research
Scripps Research Institute (US), Cincinnati Children's Hospital Medical Center (US), Roswell Park Comprehensive Cancer Center (US), Alabama Department of Public Health (US), University of Wisconsin–Madison (US), University of Arizona (US), Washington University in St. Louis (US), Jianghan University (CN), University of Alabama at Birmingham (US), North West Agriculture and Forestry University (CN), First Affiliated Hospital of Guangzhou Medical University (CN), Gansu Provincial Hospital (CN), Anna Needs Neuroblastoma Answers (US), State Key Laboratory of Respiratory Disease (CN), Indiana University – Purdue University Indianapolis (US), Vanderbilt University Medical Center (US), Guangzhou Medical University (CN)
Good health and well-being
Openalex Percentile: Top 9%
Pulmonary Hypertension Research and Treatments
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