Page 80 - GTM-1-2

Global Translational Medicine Succinate metabolism in CVD

inflammatory macrophages . In macrophages, IFN-β it leads to the formation of calcium oxalate. The transport
[43]
antagonizes JMJD3-IRF4 pathway by controlling the of citric and oxalic acids is regulated by the citric and
ratio of α-ketoglutaric acid to succinate, thus regulating succinate transporter protein Na -dependent dicarboxylate
+
the activation and polarization of macrophages . In (NaDC)-1 and the oxalic acid transporter protein SLC
[44]
the tumor microenvironment, macrophages are the family 26 member 6 (SLC26A6), both of which form a
main cells, and cancer cells secrete succinate, activate complex. This mechanism regulates the transepithelial
SUCNR1, induce M2 polarization of macrophages into transport of succinate. In SLC26A6 knockout mice, calcium
tumor-related macrophages, and increase macrophage oxalate stones, hyperoxaluria, and hypocitraturia are
migration . Succinate pre-treatment enhances IL-1β and often seen with impaired succinate homeostasis, elevated
[45]
pro-IL-1β levels in LPS-stimulated bone marrow-derived serum succinate levels, and elevated plasma renin levels,
macrophages and increases HIF-1α levels. Moreover, the exhibiting activity-dependent hypertension. Succinate acts
oxidation of succinate produces mitochondrial ROS, which on SUCNR1 to induce the translocation of the scaffold
[43]
affects the inflammatory phenotype of macrophages . protein IRBIT and regulate transepithelial succinate
There is significant evidence showing that succinate transport. IRBIT interacts with SLC26A6-NADC1 complex
[52]
increases the level of ROS, promotes vascular endothelial to inhibit NADC1-mediated succinate transport . In
cell pyroptosis and macrophage polarization, and addition, oxidative stress is an important mechanism in the
ultimately worsens atherosclerosis. pathophysiology of hypertension, and succinate is known
to aggravate oxidative stress in vivo by activating HIF-1α,
[24]
3.2. Succinate and AAD thus leading to hypertension . At present, the molecular
mechanism by which succinate activates RAS is not well
AAD occurs when the arterial wall is unable to withstand understood; however, the succinate-SUCNR1 signaling
high pressure in the blood vessel, resulting in the tearing of pathway and succinate transport mechanism may become
the middle membrane and the formation of a false lumen
(arterial dissection). Once it tears, the mortality is as high potential therapeutic targets for hypertension.
as 65 – 85% . Untargeted metabolomics studies showed 3.4. Succinate and MIRI
[46]
that the level of succinate in plasma was significantly
higher in patients with AAD. The direct phosphorylation Ischemic heart disease is the leading cause of CVD-related
of cAMP-response element-binding protein (CREB) by deaths. The main treatment strategy is to restore blood
P38α in inflammatory macrophages leads to an increase in flow to the ischemic area in a timely and effective manner,
CREB-mediated transcription of OGDH and an elevated but reperfusion itself may also lead to myocardial tissue
succinate level. The secretion of succinate outside cells injury, which is known as MIRI.
leads to an increase in ROS levels in the vascular wall, The release of succinate during reperfusion is mediated
which aggravates the progress of AAD . by MCT1. In ischemic cardiomyocytes, the intracellular
[47]
environment acidifies, and succinate transforms into a
3.3. Succinate and hypertension protonated monocarboxylic form. During reperfusion,
Hypertension is an independent risk factor for succinate monocarboxylate flows out of cells through
cardiovascular disease. Succinate plays an important role in MCT1, resulting is a reduction in intracellular succinate
the regulation of blood pressure and is closely related to the levels . Blocking MCT1 causes succinate to reside in
[28]
renin-angiotensin system (RAS). Succinate activates RAS cells, thus exacerbating ROS production and IR injury .
[53]
through SUCNR1 in the kidney to mediate hypertension . Under hypoxic and ischemic conditions, myocardial
[30]
High glucose levels stimulate the paracrine apparatus in extracellular succinate accumulation increases the
the glomerulus and trigger the release of renin through translocation of dynamin-related protein 1 (Drp1) to
the activation of succinate and its receptor SUCNR1 . mitochondria by SUCNR1 activation of protein kinase C-δ
[48]
SUCNR1, which is present in macula densa cells, is (PKCδ) and induces the phosphorylation of mitochondrial
activated by succinate and regulates renin release . The fission factor (MFF) by extracellular signal-regulated
[49]
intravenous administration of succinate increases plasma protein kinases 1 and 2 (ERK1/2) activation, leading to
renin activity and leads to a dose-dependent increase in mitochondrial fission . Succinate drives ROS production
[54]
blood pressure. This can be prevented with angiotensin- during reperfusion. Preventing succinate accumulation or
converting enzyme inhibitors . In another study, the level oxidation is a therapeutic target for cardioprotection .
[55]
[50]
of succinate in the blood of spontaneously hypertensive Elevated levels of succinate inhibit the proliferation and
rats was found higher than that of normotensive rats . regeneration of neonatal mouse cardiomyocytes through
[51]
A new succinate homeostatic pathway, which may be SDH, while malonic acid (a competitive inhibitor of
associated with hypertension, has also been identified, as SDH) inhibits the activity of SDH, preventing succinate

Volume 1 Issue 2 (2022) 5 https://doi.org/10.36922/gtm.v1i2.160