New Insights for BPIFB4 in Cardiovascular Therapy

Abstract

Aging is the most relevant risk factor for cardiovascular diseases which are the main cause of mortality in industrialized countries. In this context, there is a progressive loss of cardiovascular homeostasis that translates in illness and death. The study of long living individuals (LLIs), which show compression of morbidity toward the end of their life, is a valuable approach to find the key to delay aging and postpone associate cardiovascular events. A contribution to the age-related decline of cardiovascular system (CVS) comes from the immune system; indeed, it is dysfunctional during aging, a process described as immunosenescence and comprises the combination of several processes overpowering both innate and adaptative immune system. We have recently discovered a longevity-associated variant (LAV) in bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4), which is a secreted protein able to enhance endothelial function through endothelial nitric oxide synthase (eNOS) activation and capable to protect from hypertension, atherosclerosis, diabetic cardiopathy, frailty, and inflammaging. Here, we sum up the state of the art of the mechanisms involved in the main pathological processes related to CVD (atherosclerosis, aging, diabetic cardiopathy, and frailty) and shed light on the therapeutic effects of LAV-BPIFB4 in these contexts.

The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients’ Lymphocytes Favoring Chemotherapy Efficacy

“…Among the plethora of the immunosuppressive mechanisms, T-cell senescence and exhaustion in response to persistent cancer cell stimulation represent another major driver of dysfunctional immune responses of the GBM and of many other cancers [ 27 , 50 ]. The occurrence of this event is accentuated in elderly patients having a higher number of senescent T cells and thymic shrinkage; this might explain why the LAV haplotype in the BPIFB4 gene, selected by evolutionary forces [ 38 ] and able to counteract the age-related decline, was also effective in reversing the T-cell senescence in PBMCs from GBM patients ( Figure 4 ). No changes in peripheral monocytes’ phenotype were reported in our experimental setting ( Supplementary Materials Figure S3 ).…”

“…In these contexts, LAV-BPIFB4 demonstrates a regulatory role in the immune system’s remodeling/adaptation and the recovery of the inflammatory balance mirroring what occurs in LLIs. LAV-BPIFB4 regulates the macrophages pro-resolving M2-like polarization state (both in microglia and atherosclerotic plaque) and improves the inflammatory balance (i.e., reduces IL-1β and TNF-α levels and increases IL-33 levels in atherosclerotic process but also increases IL-1β and IL-18 levels to contrast SARS-CoV-2 infection) [ 38 ]. Definitively, LAV-BPIFB4 exerts a balancing action to finely tune the age-induced immunological dysfunction [ 39 ].…”

Adaptive Immune Responses in Human Atherosclerosis

“…Additionally, intraplaque CD4 + T-cells displayed a more activated profile (i.e., increased HLA-DR expression) [16], suggesting the presence of foreign antigens within plaques. Using mass cytometry and single-cell RNA sequencing analyses, CD4 + T-cells in atherosclerotic plaques from symptomatic (stroke) patients displayed gene expression profiles consistent with activation, differentiation, and exhaustion whereas CD4 + T-cells were mostly activated in plaques from asymptomatic (no recent stroke) patients [17].…”

“…Plaques were found to be enriched for CD8 + T-cells that were primarily T EM cells, displayed an activated phenotype, and expressed IFNγ, IL-2, or IL-17 [16]. Likewise, using mass cytometry and single-cell RNA sequencing analyses, Fernandez et al reported plaque-derived CD8 + T-cells were predominantly differentiated and activated and displayed evidence of clonal expansion [17]. A recent study demonstrated an inverse correlation between percentages of CD8 + T-cells and macrophages in advanced plaques [35].…”

BPIFB4 Circulating Levels and Its Prognostic Relevance in COVID-19

“…This allowed us to speculate a protective role against cardiovascular effects of aging. Indeed a longevity-associated variant of the BPIFB4 (LAV-BPIFB4) demonstrated a pleiotropic activity to maintain cellular homeostasis and vessel endothelium integrity along with a surprising capability to orchestrate a balanced immune response ( 17 ). Regarding the latter, LAV-BPIFB4 drives a protective macrophage-polarizing effect toward a pro-resolving M2 phenotype coupled with an improvement of the inflammatory arm (ie, reduced IL-1β and TNF-α levels and increased IL-33 levels) ( 18 ) and redirects peripheral monocyte differentiation into regulatory dendritic cells that can counteract the low-grade chronic inflammatory condition ( 14 ).…”