Hydrogen sulfide as a new therapeutic target of pulmonary hypertension: an overview with update on immunomodulation

Abstract

Pulmonary hypertension (PH) is a complex and progressive vascular disease characterized by elevated pulmonary arterial pressure (PAP) and vascular resistance, leading to right ventricular failure and, ultimately, death. Current therapies primarily focus on vasodilation and symptom management, but there remains a critical need for treatments that address the underlying pathophysiological mechanisms of PH. Numerous studies have identified hydrogen sulfide (H₂S) as a potential therapeutic target in PH. Traditionally recognized for its toxic effects at high concentrations, H₂S is now known to play crucial roles in various physiological processes, including vasodilation, anti-inflammation, and antioxidation, which are relevant to PH pathogenesis. Given its multifaceted roles in the pathophysiology of PH, H₂S represents a promising therapeutic target. Strategies to enhance endogenous H₂S production or administer exogenous H₂S donors are being explored as potential treatments for PH. These approaches aim to harness the vasodilatory, anti-inflammatory, antioxidant, and anti-remodeling properties of H₂S to mitigate disease progression and improve patient outcomes. Future research should focus on optimizing H₂S-based therapies and exploring their clinical efficacy and safety in PH patients.

Keywords: hydrogen sulfide; immunomodulation; organosulfur compounds; oxidative stress; pulmonary hypertension.

FIGURE 1

Role of VSMC dysfunction in pulmonary vascular remodeling and PH. In the pulmonary circulation, the heterogeneity and phenotypic plasticity of vascular smooth muscle cells (VSMCs) are crucial for maintaining vascular function in the lungs. Quiescent pulmonary VSMCs exhibit a contractile phenotype, characterized by low extracellular matrix (ECM) synthesis and a fusiform shape, representing their differentiated state. In response to hypoxia, growth factors, inflammatory mediators, pulmonary VSMCs transition from a contractile to a synthetic phenotype. This change is marked by increased proliferation, migration, and ECM synthesis, along with the development of PH.

FIGURE 2

There are four known pathways for H₂S decomposition in mammal system.

FIGURE 3

Involvement of cytokines and chemokines in PH.

FIGURE 4

The signaling pathways involved in the protection of H₂S against PH. H₂S ameliorated PH by decreasing endogenous production of NO and the expression of NOS and elevating the HO-1/CO pathway in pulmonary arteries. H₂S may inhibit hypoxia-induced proliferation of pulmonary VSMCs and mitigate PH by upregulating the COX-2/PGI2 signaling pathway. H₂S was reported to inhibit ATF6 and mitigate the hypoxia-induced decline in mitochondrial calcium levels. H₂S effectively inhibits hypoxia-induced proliferation, migration, oxidative stress, and ER stress of pulmonary VSMCs. H₂S reduced pulmonary artery pressure, reversed pulmonary vascular structural remolding by suppressing phosphorylation of NF-κB p65 and IκBα, thus downregulating the levels of downstream inflammatory factors, including ICAM-1, TNF-α, and IL-6 in pulmonary endothelial cells. H₂S induced the apoptosis of pulmonary VSMCs by activating the Fas/caspase3 pathway and inhibiting the Bcl-2 pathway, thereby ameliorating high pulmonary blood flow-induced PH.