Smyd3-PARP16 axis accelerates unfolded protein response and vascular aging

Area of Science:

• Molecular Biology
• Aging Research
• Vascular Biology

Background:

• Vascular endothelial cell senescence and endoplasmic reticulum (ER) stress, leading to the unfolded protein response (UPR), are key aging factors.
• The interplay between these processes and their shared upstream regulators in vascular aging remain largely unexplored.

Purpose of the Study:

• To investigate the potential crosstalk between vascular endothelial cell senescence and ER stress-induced UPR.
• To identify novel upstream regulators controlling these interconnected aging mechanisms.

Main Methods:

• Utilized cell and mouse models of angiotensin II (Ang II)-induced vascular aging.
• Investigated the role of Poly (ADP-ribose) polymerases 16 (PARP16) and its regulator Smyd3.
• Employed epigenetic analysis, including H3K4me3 level assessment, to understand gene regulation.

Main Results:

• Identified PARP16, an ER-resident protein, as upregulated in vascular aging and a promoter of UPR.
• Demonstrated that Smyd3 epigenetically upregulates PARP16 transcription via H3K4 trimethylation.
• Showed that inhibiting either Smyd3 or PARP16 ameliorates vascular aging phenotypes in vitro and in vivo.

Conclusions:

• Established the Smyd3-PARP16 signaling axis as a novel regulator of UPR and endothelial senescence.
• Highlighted the therapeutic potential of targeting this axis for preventing vascular aging and associated diseases.