Abstract: TH-PO0800
Loss of Indoleamine 2,3-Dioxygenase 1 Activity Protects Against Peripheral Artery Disease in a Murine Model of Cardiovascular-Kidney-Metabolic (CKM) Syndrome
Session Information
- CKM Axis: Vascular Dysfunction, Atherosclerosis, and Heart Failure in Kidney Diseases
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 601 Cardiovascular-Kidney-Metabolic Health: Basic
Authors
- Ranga, Arathi, Boston University, Boston, Massachusetts, United States
- Lotfollahzadeh, Saran, Boston University, Boston, Massachusetts, United States
- Bonifacio, Joshua, Boston University, Boston, Massachusetts, United States
- Almiron, Ricardo, Boston University, Boston, Massachusetts, United States
- Earthman, Gillian, Boston University, Boston, Massachusetts, United States
- Patel, Arjun M., Boston University, Boston, Massachusetts, United States
- Natrakul, Anna, Boston University, Boston, Massachusetts, United States
- Siracuse, Jeffrey, Boston University, Boston, Massachusetts, United States
- Chitalia, Vipul C., Boston University, Boston, Massachusetts, United States
Background
CKM syndrome represents a growing public health crisis driven by the convergence of obesity, chronic kidney disease, and cardiovascular disease. Peripheral artery disease (PAD) is the most debilitating vascular manifestation of CKM, associated with impaired mobility, cardiovascular events, gangrene, and limb amputation. However, PAD remains an under investigated manifestation of CKM. The molecular mechanisms linking CKM to impaired ischemic recovery in PAD remain poorly defined. Our previous work identified kynurenine, a tryptophan-derived uremic toxin, as a potent mediator of impaired angiogenesis and adverse limb events in humans. We posited that Indoleamine 2,3-dioxygenase 1 (IDO1), the rate-limiting enzyme in kynurenine biosynthesis, may represent a critical mechanistic link between CKM syndrome and PAD progression.
Methods
Male and female global IDO1 knockout (gKO) mice and wild-type littermates were subjected to a CKM-inducing diet for six weeks followed by hindlimb ischemia. Serial laser Doppler perfusion imaging, treadmill endurance, post-exercise hyperemia, grip strength and endothelial cell abundance were examined.
Results
The ischemic muscle from CKM mice showed 1-5-fold increase in IDO1 expression compared to controls. Compared with wild-type CKM male mice, IDO1 gKO CKM mice demonstrated a 30% increase in hindlimb perfusion recovery (P=0.0073) and functional performance - a 20% increase in post-exercise hyperemia, a 1.25-fold increase in distance traveled (P=0.0278), a 2-fold increase in time to exhaustion (P=0.0364), and significantly greater grip strength (P=0.0193). Female IDO1 gKO CKM mice exhibited an even more pronounced improvement in perfusion recovery (P=0.0176), exercise endurance (distance traveled, P=0.0124; exhaustion time, P=0.015), and grip strength (P=0.0189) compared to controls. Ischemic soleus muscle demonstrated increased endothelial content in IDO1-KO mice, consistent with enhanced angiogenic remodeling and microvascular recovery.
Conclusion
These findings identify IDO1 as a critical metabolic and inflammatory mediator of PAD in CKM and support further probing IDO1 as a mechanistic link between the kynurenine pathway and CKM-associated PAD. Targeting IDO1 may represent a translational strategy to improve adverse limb events in patients with CKM syndrome and PAD.