Long-term cardiovascular complications following sepsis: is senescence the missing link?

Abstract

Among the long-term consequences of sepsis (also termed "post-sepsis syndrome") the increased risk of unexplained cardiovascular complications, such as myocardial infarction, acute heart failure or stroke, is one of the emerging specific health concerns. The vascular accelerated ageing also named premature senescence is a potential mechanism contributing to atherothrombosis, consequently leading to cardiovascular events. Indeed, vascular senescence-associated major adverse cardiovascular events (MACE) are a potential feature in sepsis survivors and of the elderly at cardiovascular risk. In these patients, accelerated vascular senescence could be one of the potential facilitating mechanisms. This review will focus on premature senescence in sepsis regardless of age. It will highlight and refine the potential relationships between sepsis and accelerated vascular senescence. In particular, key cellular mechanisms contributing to cardiovascular events in post-sepsis syndrome will be highlighted, and potential therapeutic strategies to reduce the cardiovascular risk will be further discussed.

Keywords: Atherosclerosis; Sepsis; Septic shock; Stress-induced premature senescence (SIPS).

Fig. 1

Potential mechanisms contributing to endothelial senescence-driven cardiovascular complications after sepsis and septic shock. Sepsis and septic shock survivors have an increased risk of developing cardiovascular events such as myocardial infarction and stroke. Sepsis-induced premature senescence could explain an accelerated atherogenesis process leading to early major adverse cardiovascular events. SASP senescence-associated secretory phenotype

Fig. 2

Difference between senescence and apoptosis. Intermediate stress can lead to senescence via p53 and p16 pathway, resulting in persisting cell dysfunction. High cellular stress can induce apoptosis through upregulation of p53, resulting to cell death and elimination. High level of p53 contributes to the induction of BH3-only proteins (BIM, PUMA, NOXA) that inhibits pro-survival BCL-2 family members (BCL-XL, MCL-1, BCL 2)

Fig. 3

Characteristics of senescent endothelial cell. Senescent cells become irregular and flat with cytoplasmic and nuclear enlargement, multiple organelle modifications, including enlarged and dysfunctional lysosomes enclosing lipid and protein aggregates. Senescent cells can exhibit hyperelongated mitochondria resulting from unbalanced mitochondrial fission and fusion thereby favoring ROS generation. An expanded Golgi apparatus is also observed, along with nuclear enlargement and chromatin condensation such as SAHF. Senescence-associated dysfunction includes the SASP with autocrine and paracrine effects, the apoptosis resistance and cell cycle arrest. ROS reactive oxygen species, SAHF senescence-associated heterochromatin foci, SASP senescence-associated secretory phenotype

Fig. 4

Features of dysfunctional senescent endothelial cell. Accumulation of senescent endothelial cells impedes vascular homeostasis. Main consequences include a progressive acquisition of an inflammatory endothelial phenotype, a procoagulant state, a proatherogenic phenotype, and the loss of vascular tone with reduced NO availability and increased release of endothelin. NO nitric oxide

Fig. 5

Main pathways leading to cellular senescence. Mechanisms that drive cellular senescence include the direct activation of the DNA damage response (DDR) through the ATM/ATR pathway and/or of the INK4a/ARF locus through the assembly of PcG protein complexes eventually via the ANRIL scaffolding Lnc RNA. The INK4 family, among which p16, are cyclin-dependent kinase inhibitors targeting CDK4/6. Ultimately, p53/p21 and p16/Rb pathways are key players driving senescence. ANRIL: antisense non-coding RNA in the INK4 locus, ARF ADP ribosylation factor, ARHGAP18 (Rho GTPase activating protein 18), ATM ataxia-telangiectasia mutated, ATR ataxia-telangiectasia mutated and Rad3 related, CDKs cyclin-dependent kinases, Chk1 checkpoint kinase 1, Chk2 checkpoint kinase 2, DDR DNA damage response, INK4 inhibitors of CDK4, p16/Rb p16/retinoblastoma protein, PcG polycomb, Lnc RNA long non-coding RNA, ROS reactive oxygen species

Fig. 6

Main senotherapeutic drug targets. Senolytics aiming to eliminate senescent cells favor downstream apoptosis or directly target senescent lysosomes (SSK1). Senostatics preventing the acquisition of a senescent state limit the conversion of quiescent cells, the progressive acquisition of SASP and the inhibition of SENEX. SASP senescence-associated secretory phenotype, SSK1 senescence-specific killing compound 1