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Global Translational Medicine Succinate metabolism in CVD

Although both compounds have poor bioavailability, Table 1. Potential therapeutic targets of succinate
they significantly alleviated hypertension in rats induced metabolism
by succinate intervention. The study also screened several Treatment Name of Species EC50/IC50 References
compounds with good bioavailability but poor specificity compound
and used another compound (2d) for intervention. The 2d SUCNR1 cis-Epoxysuccinic Rat 2.7 μM [78]
can inhibit the expression of type I collagen in rat hepatic agonist acid
stellate cells induced by high glucose or succinate , SUCNR1 2c Human/Rat 30 nM [79]
[80]
suggesting that it may play a certain role in alleviating inhibitor 4c 7 nM
non-alcoholic fatty liver. High-throughput screening 2d Rat 40 nM [80]
identified another compound, NF-56-EJ40, which may NF-56-EJ40 Human 25 nM [31]
be used as an inhibitor of SUCNR1. Its IC50 for human
[31]
SUCNR1 is 25 nM, indicating good performance . mRNA miR-758 Mouse [83]
Through further crystal structure analysis, the structural
basis of species differences in this inhibition has been Due to the complex environment-dependent functions
clarified, thus providing direction for the design and of SUCNR1, its current research is not thorough enough.
selection of inhibitors in the future. The inhibitors Despite the fact that large pharmaceutical companies
studied in the previous stage have poor permeability due have submitted patents for screening SUCNR1 regulatory
to their polar zwitterionic properties. Hence, to design drugs or using SUCNR1 as an immune cell marker, it does
effective drugs with good bioavailability, recent studies not seem to have received enough attention. At present,
have systematically optimized them by adding internal several research groups and small companies are exploring
salt bridges. superior performance regulators of SUCNR1 and their
The therapeutic effect of the SUCNR1 inhibitor has applications in diseases, but more research is needed
not been reported at present. However, the designer of the to explain its complex functions and important role in
SUCNR1 inhibitor based on naphthyridine has applied diseases.
for a series of patents, in which it has been alluded that 5. Conclusion and perspectives
SUCNR1 inhibitor may be used in the treatment of non-
alcoholic fatty liver disease and other related diseases, Numerous clinical diagnoses of CVD have revealed
revealing a certain potential therapeutic value. Fibroblast changes in succinate levels. Succinate is regarded as
growth factor 21 and co-recombinant peptide analogs a potential biomarker of CVD. The accumulation of
have been found to inhibit the production of α-smooth succinate in ischemic tissues indicates the presence of
[24]
muscle actin and reduce fibrosis in mice by inhibiting ischemia . Elevated plasma succinate levels are associated
the succinate-SUCNR1 signaling pathway . Metformin, with increased cardiovascular risk factors in young adults,
[81]
a miracle drug for the treatment of type 2 diabetes, has and its levels are positively correlated with visceral adipose
also been shown to inhibit the hepatic succinate-SUCNR1 tissue mass, which may serve as a biomarker for CVD
signaling pathway . risk in young adults . Serum succinate was found to
[85]
[82]
be significantly elevated in patients with coronary heart
Exploring the decrease in SUCNR1 expression at the [40]
mRNA level is also an important means for researchers disease compared with healthy controls . Circulating
to explore the succinate-SUCNR1 signaling pathway. succinate levels are elevated in obese patients and are
associated with poor metabolic status . In patients with
[86]
SUCNR1 is an important target of microRNA (miR)- ST-elevation myocardial infarction, the level of succinate
758. Oxidized low-density lipoprotein stimulates the [43]
expression of miR-758 in endothelial cells and further in the coronary sinus increases significantly . Serum
downregulates SUCNR1 and its downstream signaling succinate levels also increase in patients with cardiac
hypertrophy associated with acute or chronic obstructive
pathway, resulting in human vascular endothelial cell [62]
injury . In a rat retinopathy model, the knockdown of coronary artery disease . Early AAD is usually
[83]
rat SUCNR1 by small interfering RNA (siRNA) resulted asymptomatic; hence, it is a challenge for an early diagnosis
in decreased vascular endothelial growth factor secretion, to be made. Since plasma succinate levels are significantly
abnormal neovascularization, loss of pericytes, and areas elevated in patients with AAD, it can be used to distinguish
without blood vessels . The optimization of the structure AAD from patients with acute myocardial infarction and
[84]
[47]
and pharmacokinetics of SUCNR1 inhibitors enables pulmonary embolism .
researchers to identify new compounds and verify them in This review focuses on the mechanism of succinate
animal models (Table 1). metabolism and its related factors in CVD. The existing

Volume 1 Issue 2 (2022) 8 https://doi.org/10.36922/gtm.v1i2.160