Super-Enhancer-Driven Syndecan-4 Regulates Intercellular Communication in Hypoxic Pulmonary Hypertension

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cellular Signaling

Background:

• Pulmonary hypertension (PH) involves complex cellular crosstalk.
• Super-enhancers (SEs) regulate pathological processes, but their role in PH is unclear.
• Identifying SE-associated genes is crucial for PH therapeutics.

Purpose of the Study:

• To identify novel SE-associated genes in pulmonary hypertension.
• To investigate the role of syndecan-4 (SDC4) in PH pathogenesis.
• To explore SDC4's mechanism in cell-cell communication and vascular remodeling.

Main Methods:

• Constructed a hypoxia-induced PH model with SU5416.
• Utilized ChIP-sequencing and qPCR to identify SE-associated genes.
• Employed Western blot, co-immunoprecipitation, and cell coculture assays to elucidate mechanisms.

Main Results:

• Identified syndecan-4 (SDC4) as a novel SE-associated gene in hypoxic PASMCs.
• SDC4 is transcriptionally regulated by early growth response 1 (EGR1) via an SE.
• SDC4 overexpression in hypoxic PASMCs and PH patient plasma; SDC4 induces PASMC proliferation via PKCα ubiquitination and promotes endothelial dysfunction via exosomes.

Conclusions:

• SE-driven SDC4 modulates PASMC and endothelial cell crosstalk in PH.
• SDC4 promotes vascular remodeling through PKCα and exosome pathways.
• SDC4 represents a potential therapeutic target for hypoxic PH.