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Published on: February 11, 2017
A Paradigm Shift of H2S Donors in Pulmonary Arterial Hypertension Toward Precision Delivery, Endogenous Activation,
Shuang Gao1, Xin Chen2, Chunyuan Zhang2
1Graduate School, Heilongjiang University of Chinese Medicine, Harbin 150040, China.
First-generation H2S donors fail in pulmonary arterial hypertension (PAH) not due to lack of efficacy, but because they release H2S indiscriminately. This review articulates a conceptual framework for advancing H2S donor therapy along three complementary directions. Donor 2.0 for precision delivery: Donors remain inert in normal tissues, but release H2S upon sensing PAH microenvironment signals [reactive oxygen species (ROS), hypoxia, esterases, matrix metalloproteinases (MMPs)], combined with lesion-selective enrichment and organelle targeting. Donor-endogenous synergy: Move from chronic exogenous supplementation to restoring the patient's own H2S synthesis via epigenetic derepression of CSE, oxidative reactivation of CBS, and substrate support for 3-MST. Systemic sensitization: Redefine H2S donors as combination enhancers that reverse acquired insensitivity to ERAs, PDE5i, and prostacyclin analogues through protein S-sulfhydration. These three mutually reinforcing dimensions transform H2S donors from passive releasers into programmable, context-sensitive therapeutic platforms, addressing the fundamental limitations of current PAH therapies.
First-generation H2S donors fail in pulmonary arterial hypertension (PAH) not due to lack of efficacy, but because they release H2S indiscriminately. This review articulates a conceptual framework for advancing H2S donor therapy along three complementary directions. Donor 2.0 for precision delivery: Donors remain inert in normal tissues, but release H2S upon sensing PAH microenvironment signals [reactive oxygen species (ROS), hypoxia, esterases, matrix metalloproteinases (MMPs)], combined with lesion-selective enrichment and organelle targeting. Donor-endogenous synergy: Move from chronic exogenous supplementation to restoring the patient's own H2S synthesis via epigenetic derepression of CSE, oxidative reactivation of CBS, and substrate support for 3-MST. Systemic sensitization: Redefine H2S donors as combination enhancers that reverse acquired insensitivity to ERAs, PDE5i, and prostacyclin analogues through protein S-sulfhydration. These three mutually reinforcing dimensions transform H2S donors from passive releasers into programmable, context-sensitive therapeutic platforms, addressing the fundamental limitations of current PAH therapies.
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