Page 79 - GTM-1-2

Global Translational Medicine Succinate metabolism in CVD

resulted in the expansion of Th17 cells, which, further, led
to autoimmune diseases .
[34]
In addition to its effect on chemotaxis, SUCNR1 also
plays an important role in macrophage inflammation.
However, there are conflicting results in the current
research. SUCNR1 plays a pro-inflammatory role in M2
macrophages derived from human peripheral blood
monocytes. IL-4 or IL-10 stimulates macrophages,
resulting in the upregulation of SUCNR1 expression in
macrophages. However, the treatment of macrophages
with succinate or SUCNR1 agonists decreases the secretion
of IL-10 and increases TNF-α expression in macrophages,
thus enhancing the inflammatory response .
[35]
Macrophages are activated by inflammatory signals
release succinate to the extracellular environment, activate
SUCNR1 through autocrine and paracrine signaling, and
promote the production of IL-1β, thus further aggravating
tissue inflammation . Although the previous studies Figure 1. Succinate metabolism and transport. The main source
[36]
have shown that the knockout of SUCNR1 does not affect of succinate is the oxidative decarboxylation of α-ketoglutarate by
the secretion of IL-1β, TNF-α, and IL-6 in peritoneal oxoglutarate dehydrogenase in the tricarboxylic acid cycle to form
[37]
macrophages stimulated by LPS (10 ng/mL, 24 h) , succinyl-coenzyme (Co)A, which is catalyzed by succinyl-CoA synthase
to generate succinate. The other source of succinate is derived from the
another study found that SUCNR1 knockdown resulted in metabolism of intestinal flora through the fermentation of dietary fiber.
a significant decrease in IL-1β expression in bone marrow- Succinate generates excessive reactive oxygen species during oxidation.
derived macrophages (BMDMs) when stimulated with a The metabolic pathway of succinate includes the oxidation to fumaric
higher dose (100 ng/mL) of LPS. IL-1β stimulation results acid in the presence of SDH and then protonation due to the decrease
in mitochondrial pH. Succinate is transported to the extracellular level
[36]
in an increased expression of SUCNR1 in BMDMs . through SLC25A10 and monocarboxylic acid transporter 1.
These results indicate that there may be some positive
feedback between SUCNR1 and inflammatory cytokines. certain conditions, such as hypoxia and tissue injury .
[39]
Other studies have shown that LPS-stimulated BMDMs of Succinate accumulates in ischemic tissues and is involved
SUCNR1 knockout mice had increased IL-6, TNF-α, and in perfusion injury through mitochondrial ROS . The
[24]
nitric oxide (NO) release compared to the control group . binding of succinate to SUCNR1, which is expressed in
[38]
This finding reveals that SUCNR1 may play an anti- human umbilical vein endothelial cells (HUVECs) and
inflammatory role, thus contradicting previous studies. macrophages, activates transcription factor hypoxia-
Hence, the mechanism needs to be further explored. inducible factor (HIF)-1α, stimulates the succinate/IL-1β
In conclusion, succinate is generated and transported signaling axis, promotes the expression of IL-1β to produce
through various pathways, and it plays different roles, excess pro-inflammatory cytokines, and exacerbates the
depending on physiological and pathological conditions inflammatory process of atherosclerosis [23,40] .
(Figure 1). Enzymes, intermediate metabolites involved in SDHB is one of the six subunits of the succinate
succinate metabolism, or SUCNR1 may become potential dehydrogenase complex. Low shear stress downregulates
therapeutic targets for CVD in the future.
the expression of tet methylcytosine dioxygenase 2,
3. Succinate and cardiovascular disease inhibits the recruitment of histone deacetylase 2, and
upregulates the expression of SDHB. SDHB mediates
3.1. Succinate and atherosclerosis mitochondrial damage, increases the production of
The pathophysiological mechanism of atherosclerosis ROS, and subsequently induces vascular endothelial cell
involves inflammatory response, endothelial cell pyroptosis . Trimethylamine N-oxide (TMAO) promotes
[41]
dysfunction, and macrophage polarization, all of which the production of ROS in HUVECs and endothelial cell
eventually lead to plaque formation. pyroptosis by upregulating the expression of SDHB .
[42]
Succinate acts as an inflammatory signal ligand, which Succinate in mitochondria generates a large
can be transmitted through the receptor SUCNR1. SUCNR1 amount of ROS through the oxidation of SDH, which
is inactive in normal tissues and can be activated under promotes the conversion of macrophages into M1 pro-

Volume 1 Issue 2 (2022) 4 https://doi.org/10.36922/gtm.v1i2.160