Endothelial and systemic upregulation of miR-34a-5p fine-tunes senescence in progeria

Abstract

Endothelial defects significantly contribute to cardiovascular pathology in the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Using an endothelium-specific progeria mouse model, we identify a novel, endothelium-specific microRNA (miR) signature linked to the p53-senescence pathway and a senescence-associated secretory phenotype (SASP). Progerin-expressing endothelial cells exert profound cell-non-autonomous effects initiating senescence in non-endothelial cell populations and causing immune cell infiltrates around blood vessels. Comparative miR expression analyses revealed unique upregulation of senescence-associated miR34a-5p in endothelial cells with strong accumulation at atheroprone aortic arch regions but also, in whole cardiac- and lung tissues as well as in the circulation of progeria mice. Mechanistically, miR34a-5p knockdown reduced not only p53 levels but also late-stage senescence regulator p16 with no effect on p21 levels, while p53 knockdown reduced miR34a-5p and partially rescued p21-mediated cell cycle inhibition with a moderate effect on SASP. These data demonstrate that miR34a-5p reinforces two separate senescence regulating branches in progerin-expressing endothelial cells, the p53- and p16-associated pathways, which synergistically maintain a senescence phenotype that contributes to cardiovascular pathology. Thus, the key function of circulatory miR34a-5p in endothelial dysfunction-linked cardiovascular pathology offers novel routes for diagnosis, prognosis and treatment for cardiovascular aging in HGPS and potentially geriatric patients.

Functional role of miR-34a in diabetes and frailty

“…Specifically, miR-34a has been associated to frailty, aging, and diabetes ( Figure 1 ) ( Boon et al, 2013 ; Chakraborty et al, 2014 ; Rippo et al, 2014 ; Badi et al, 2018 ; Thounaojam and Bartoli, 2019 ; Kukreti and Amuthavalli, 2020 ; Ni et al, 2020 ; Manakanatas et al, 2022 ) and is generally considered a bona fide biomarker of cellular and vascular senescence ( Badi et al, 2015 ; Park et al, 2020 ; Manakanatas et al, 2022 ).…”

Progerin triggers a phenotypic switch in vascular smooth muscle cells that causes replication stress and an aging-associated secretory signature

“…The senescence-associated secretory phenotype (SASP) is characterized by the secretion of prominent levels of inflammatory cytokines, growth factors, and proteases that play a major part in the inflammation associated with age, known as inflammaging. Progerin-expressing endothelial cells were shown to upregulate pro-inflammatory factors associated with SASP (Manakanatas et al, 2022). Using the International Cell Senescence Association Discover Genes Related to Senescence (Senequest) database, we find that the secreted proteins identified in progerin-expressing VSMC belong to the SASP (Figure 4B).…”

Ageing impairs the neuro-vascular interface in the heart

“…This suggests that endothelial senescence might contribute to neuronal repulsion or death. Indeed, the selective induction of endothelial cell senescence in young animals by endothelial-specific overexpression of progerin 30 significantly reduced the density of Tuj1 positive nerves compared to wildtype littermates ( Fig. 3h ).…”

“…Endothelial-specific progeria mice were generated as previously described 30 . Male and female mice were use at the age of 28 to 29 weeks.…”