Replacement substance P reduces cardiac fibrosis in monkeys with type 2 diabetes - 26/02/23
, Kylie Kavanagh b, c, Nazli Gharraee a, Jessica L. Lacy a, Kevin H. Goslen d, Masha Block b, Jordyn Whitfield b, Alexander Widiapradja e, f, g, Scott P. Levick e, f, gAbstract |
Background |
Type 2 diabetes mellitus (T2DM)-associated cardiac fibrosis contributes to heart failure. We previously showed that diabetic mice with cardiomyopathy, including cardiac fibrosis, exhibit low levels of the neuropeptide substance P; exogenous replacement of substance P reversed cardiac fibrosis, independent of body weight, blood glucose and blood pressure. We sought to elucidate the effectiveness and safety of replacement substance P to ameliorate or reverse cardiac fibrosis in type 2 diabetic monkeys.
Methods |
Four female T2DM African Green monkeys receive substance P (0.5 mg/Kg/day S.Q. injection) for 8 weeks. We obtained cardiac magnetic resonance imaging and blood samples to assess left ventricular function and fibrosis by T1 map-derived extracellular volume as well as circulating procollagen type I C-terminal propeptide. Hematological parameters for toxicities were also assessed in these monkeys and compared with three female T2DM monkeys receiving saline S.Q. as a safety comparison group.
Results |
Diabetic monkeys receiving replacement substance P exhibited a ∼20% decrease in extracellular volume (p = 0.01), concomitant with ∼25% decrease procollagen type I C-terminal propeptide levels (p = 0.008). Left ventricular ejection fraction was unchanged with substance P (p = 0.42); however, circumferential strain was improved (p < 0.01). Complete blood counts, glycosylated hemoglobin A1c, lipids, liver and pancreatic enzymes, and inflammation markers were unchanged (p > 0.05).
Conclusions |
Replacement substance P reversed cardiac fibrosis in a large preclinical model of type 2 diabetes, independent of glycemic control. No hematological or organ-related toxicity was associated with replacement substance P. These results strongly support a potential application for replacement substance P as safe therapy for diabetic cardiac fibrosis.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Diabetic cardiomyopathy-associated cardiac fibrosis remains a challenging phenotype. |
• | Effective anti-fibrotic therapies remain elusive and limited to stringent glycemic control. |
• | Diabetes-induced cardiac fibrosis is associated with substance P loss in cardiac nerve fibers |
• | Replacement SP represents an effective and safe therapy to reverse cardiac fibrosis |
Abbreviations : CCL2, CMR, CTL, DBP, BSA, ECV, IR, LV, LVEDVi, LVEF, LVESVi, MMP, MOLLI, Mϕ, NT-pro-BNP, PICP, PSR, PWV, SBP, SD, SP, ST2, T2DM, TNF-α
Keywords : Cardiomyopathy, Fibrosis, Heart, Non-human primate
Plan
Vol 160
Article 114365- avril 2023 Retour au numéro
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