Aortic dissection is associated with reduced polycystin-1 expression, an abnormality that leads to increased ERK...

Area of Science:

• Cardiovascular Biology
• Cellular Signaling
• Molecular Medicine

Background:

• Vascular smooth muscle cell (VSMC) phenotypic switching is central to cardiovascular diseases like aortic dissection (AD).
• Polycystin-1 (PC1) is downregulated in AD patients' VSMCs, but its role in signaling remains unclear.
• PC1 regulates cell proliferation, apoptosis, and polarity, yet its impact on VSMC phenotype is not fully elucidated.

Purpose of the Study:

• To investigate the role of Polycystin-1 (PC1) in regulating the human vascular smooth muscle cell (VSMC) phenotypic switch.
• To identify the specific intracellular signaling pathways modulated by PC1 in VSMCs.
• To explore the potential contribution of PC1 to the pathophysiology of aortic dissection (AD).

Main Methods:

• Examined protein expression changes (SM22α, ACTA2, CNN1, phospho-MEK, phospho-ERK, myc) in VSMCs with downregulated PC1.
• Utilized an ERK inhibitor to assess pathway involvement in PC1-mediated VSMC changes.
• Overexpressed the C-terminal domain (PC1 C-tail) and a specific mutant (S4166A) to evaluate PC1's functional sites.

Main Results:

• PC1 downregulation in VSMCs increased SM22α, ACTA2, CNN1, phospho-MEK, phospho-ERK, and myc expression.
• ERK inhibition reversed PC1 downregulation-induced VSMC changes.
• Overexpression of PC1 C-tail, particularly the wild-type form, downregulated these markers, while the S4166A mutant mimicked PC1 deficiency.

Conclusions:

• The MEK/ERK/myc signaling pathway mediates PC1's role in the human VSMC phenotypic switch.
• The Ser 4166 site on PC1 is critical for regulating this pathway.
• Dysregulation of the PC1-mediated MEK/ERK/myc pathway may be a key factor in aortic dissection development.