Key result
Short-chain fatty acids improve limb perfusion recovery vs vehicle in preclinical peripheral artery disease.
Why the study?
Building on findings that palmitate aggravates ischemic endothelial dysfunction in vitro, the study aimed to determine whether palmitate determines PAD severity and to investigate the role of short-chain fatty acids in regulating ischemic revascularization.
Do short-chain fatty acids improve ischemic revascularization and perfusion recovery in preclinical models of peripheral artery disease?
Do short-chain fatty acids improve ischemic revascularization and perfusion recovery in preclinical models of peripheral artery disease?
Absolute Event Rate: 0.918% vs 0.81%
p-value: p=0.044
SCFAs enhance perfusion recovery in ischemic muscle via FFAR3 activation, contrasting with the detrimental effects of palmitate on ischemic revascularization in peripheral artery disease.
SCFA perfusion recovery in mice should not yet change PAD practice; hypothesis-generating for FFAR3-targeted revascularization therapies.
Background Our current study builds on our recent report that showed Palmitate aggravates ischemic endothelial (EC) dysfunction in vitro and aims to determine whether Palmitate is a critical determinant of PAD severity. In contrast to Palmitate, we studied the role of short-chain fatty acids (SCFAs) in regulating ischemic revascularization in PAD. Methods Femoral artery ligation and resection was used as preclinical-PAD model. Hypoxia serum starvation was used as in vitro PAD model. Results Palmitate dramatically decreased ischemic-EC survival and angiogenic capacity in vitro , whereas SCFAs significantly induced their angiogenic capacity. LC-MRM MS analysis showed decreased SCFA content in ischemic-muscle. Laser Speckle perfusion imaging showed that intramuscular SCFA treatment significantly induced perfusion recovery, whereas Palmitate showed a modest but significant impairment in perfusion recovery. Immunoblot analysis showed that SCFAs preferentially induce Free fatty acid receptor (FFAR)-3, but not FFAR2. Accordingly, silencing FFAR3 decreased ischemic-EC angiogenic capacity, whereas inhibiting FFAR2 induced ischemic angiogenesis. Pharmacological inhibition of FFAR3 by beta-hydroxybutyrate (BHB) significantly decreased perfusion recovery. SCFA treatment further decreased perfusion recovery in BHB-treated ischemic-muscle. Mechanistically, inhibiting FFAR3-induced FFAR2-levels that inhibited ischemic-EC angiogenic capacity by decreasing NO and inducing ROS levels in SCFA-treated ischemic-ECs. Conclusions Our data shows that Palmitate alone is not sufficient to drive the PAD severity. Increased FFAR3 levels in ischemic-muscle allow SCFAs to activate the AKT-NO axis to induce ischemic angiogenesis and perfusion recovery. However, loss of FFAR3 in ischemic-muscle promotes FFAR2 activation that blocks SCFA-induced NO-production and redox balance thereby inhibiting perfusion recovery in preclinical-PAD.
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Kuppuswamy et al. (2025) studied Peripheral Artery Disease. Short-chain fatty acids (SCFAs) vs. Vehicle control (BSA) or Palmitate was evaluated on Perfusion recovery at day 21 post-hindlimb ischemia (p=0.044). Short-chain fatty acid treatment significantly induced perfusion recovery compared to vehicle control (0.918 vs 0.810, p=0.044), whereas Palmitate impaired perfusion recovery in a preclinical peripheral artery disease model.
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