Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2

Abstract

Cellular senescence is a key driver of ageing, influenced by age-related changes to the regulation of alternative splicing. Hydrogen sulfide (H2S) has similarly been described to influence senescence, but the pathways by which it accomplishes this are unclear.We assessed the effects of the slow release H2S donor Na-GYY4137 (100 µg/ml), and three novel mitochondria-targeted H2S donors AP39, AP123 and RT01 (10 ng/ml) on splicing factor expression, cell proliferation, apoptosis, DNA replication, DNA damage, telomere length and senescence-related secretory complex (SASP) expression in senescent primary human endothelial cells.All H2S donors produced up to a 50% drop in senescent cell load assessed at the biochemical and molecular level. Some changes were noted in the composition of senescence-related secretory complex (SASP); IL8 levels increased by 24% but proliferation was not re-established in the culture as a whole. Telomere length, apoptotic index and the extent of DNA damage were unaffected. Differential effects on splicing factor expression were observed depending on the intracellular targeting of the H2S donors. Na-GYY4137 produced a general 1.9 – 3.2-fold upregulation of splicing factor expression, whereas the mitochondria-targeted donors produced a specific 2.5 and 3.1-fold upregulation of SRSF2 and HNRNPD splicing factors only. Knockdown of SRSF2 or HNRNPD genes in treated cells rendered the cells non-responsive to H2S, and increased levels of senescence by up to 25% in untreated cells.Our data suggest that SRSF2 and HNRNPD may be implicated in endothelial cell senescence, and can be targeted by exogenous H2S. These molecules may have potential as moderators of splicing factor expression and senescence phenotypes.

Hydrogen Sulfide Inhibits Homocysteine-Induced Neuronal Senescence by Up-Regulation of SIRT1

“…Therefore, we for the first demonstrated that H 2 S prevents Hcy-induced cellular senescence in HT22 cells. It has been confirmed that H 2 S prevents the process of senescence in the endothelium [42], kidney [45,46], vascular [47], heart [48] and brain [43] of mice. Furthermore, increasing the content of endogenous H 2 S by proper diet extends the life span of the aged mice [49,50].…”

“…H 2 S, a well-known regulator of inflammation [39], ER stress [40] and cytotoxicity [41], is recognized as a new approach to prolong lifespan [12]. H 2 S has been described to prevent endothelial cell senescence [18,42] and delays aging [43]. Furthermore, we have previously found that H 2 S inhibits formaldehydeinduced cellular senescence [44] and protects against Hcy-induced neurotoxicity [25].…”

circRNAs expressed in human peripheral blood are associated with human aging phenotypes, cellular senescence and mouse lifespan

“…Early passage young cells were at population doubling (PD) of 24 for astrocytes, 28 for cardiomyocytes, 24 for endothelial cells and 25 for fibroblasts, whilst late passage senescent cells were at PD = 84 for astrocytes, 75 for cardiomyocytes, 65 for endothelial cells and 63 for fibroblasts. Senescent cell load in these samples was~75% for fibroblasts,~55% for endothelial cells,~38% for cardiomyocytes and~36% for cardiomyocytes(Latorre et al 2017; Latorre et al 2018a;Latorre et al 2018b;Latorre et al 2018c;Lye et al 2019). In all cases, growth of the culture had slowed to less than 0.5 PD/week.…”

“…Gene expression is regulated at many levels. Changes in the regulation and pattern of alternative splicing are associated with age in several human populations and are also evident in senescent cells of different lineages, where they may drive cellular senescence, since restoration of levels reverses multiple senescence phenotypes (Latorre et al 2017;Latorre et al 2018a;Latorre et al 2018b;Latorre et al 2018c;Lye et al 2019). Notably, non-coding RNAs also demonstrate associations with aging or senescence and may be of equal importance (Abdelmohsen et al 2012;Boulias and Horvitz 2012;Gorospe and Abdelmohsen 2011).…”

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

“…It was reported that mitochondria-targeted gasotransmitter hydrogen sulfide (H 2 S) delays endothelium senescence [96]. Recently, substantial evidence indicates that H 2 S exerts a potential evolutionarily conserved function of anti-vascular ageing [42].…”