A Model of Evolutionary Selection: The Cardiovascular Protective Function of the Longevity Associated Variant of BPIFB4

Abstract

Evolutionary forces select genetic variants that allow adaptation to environmental stresses. The genomes of centenarian populations could recapitulate the evolutionary adaptation model and reveal the secrets of disease resistance shown by these individuals. Indeed, longevity phenotype is supposed to have a genetic background able to survive or escape to age-related diseases. Among these, cardiovascular diseases (CVDs) are the most lethal and their major risk factor is aging and the associated frailty status. One example of genetic evolution revealed by the study of centenarians genome is the four missense Single Nucleotide Polymorphisms (SNPs) haplotype in bactericidal/permeability-increasing fold-containing family B, member 4 (BPIFB4) locus that is enriched in long living individuals: the longevity associated variant (LAV). Indeed, LAV-BPIFB4 is able to improve endothelial function and revascularization through the increase of endothelial nitric oxide synthase (eNOS) dependent nitric oxide production. This review recapitulates the beneficial effects of LAV-BPIFB4 and its therapeutic potential for the treatment of CVDs.

Keywords: BPIFB4; aging; angiogenesis; cardiovascular disease; eNOS.

Figure 1

Age-induced arterial dysfunction. (left): young elastic artery with a thin structure and functional nitric oxide synthase that result in a proper vasorelaxation (green arrow); (right): older artery with thickened intima and media and dysfunctional nitric oxide synthase that promote cardiovascular pathological conditions, such as the decrease of vasorelaxation ability and the increase of stiffness (red arrows).

Figure 2

Schematic representation of domains organization and post-translational modifications in bactericidal/permeability-increasing fold-containing family B, member 4 (BPIFB4). The figure shows BPIFB4 structure and indicates the position of phosphorylation sites, the binding sites and the post translational modifications [52].

Figure 3

Schematic mechanism of function of Longevity Associated Variant (LAV) of BPIFB4. The figure shows the schematic representation of the pathway that involves BPIFB4. The LAV isoform is retained in the cytoplasm by the enhanced interaction with 14-3-3 protein and it is phosphorylated by protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and protein kinase C alpha (PKCα). This activation leads to the phosphorylation of endothelial nitric oxide synthase (eNOS) through PKCα and through still unknown players. eNOS produces NO that is used for the activity of smooth muscle cells. Small yellow “P” circles indicate phosphorylation events.