LAV-BPIFB4 isoform modulates eNOS signalling through Ca2+/PKC-alpha-dependent mechanism

Area of Science:

• Vascular Biology
• Molecular Mechanisms of Aging
• Genetics of Longevity

Background:

• Aging impairs endothelial nitric oxide synthase (eNOS) and reduces endothelial function.
• A longevity-associated variant (LAV) in BPIFB4 (I229V) was previously identified in long-living individuals.
• LAV-BPIFB4 enhances endothelial NO production and vasorelaxation via a specific signaling pathway.

Purpose of the Study:

• To elucidate the molecular mechanisms by which LAV-BPIFB4 enhances vascular function.
• To investigate the roles of calcium, PKCα, and EDHF in LAV-BPIFB4's effects.

Main Methods:

• Overexpression of LAV-BPIFB4 in human endothelial cells.
• Assessment of Ca2+ mobilization and PKCα translocation.
• Pharmacological inhibition of PKCα.
• Experiments in Ca2+-free media and eNOS knockout mouse vessels.

Main Results:

• LAV-BPIFB4 enhances eNOS function through Ca2+ mobilization and PKCα activation.
• Overexpression of LAV-BPIFB4 increased ATP-induced Ca2+ mobilization and PKCα translocation.
• PKCα inhibition abolished the positive effects of LAV-BPIFB4 on eNOS and endothelial function.
• LAV-BPIFB4 retained its ability to potentiate endothelial activity via EDHF in the absence of eNOS or external Ca2+.

Conclusions:

• Novel molecular mechanisms for LAV-BPIFB4's beneficial effects on endothelial function were identified.
• Ca2+ mobilization and PKCα are crucial for eNOS activation by LAV-BPIFB4.
• EDHF acts as an alternative pathway when eNOS is inhibited.
• LAV-BPIFB4 may restore age-associated signaling deficits in the vasculature.