Biomedicine & Pharmacotherapy (Apr 2023)

Replacement substance P reduces cardiac fibrosis in monkeys with type 2 diabetes

  • Giselle C. Meléndez,
  • Kylie Kavanagh,
  • Nazli Gharraee,
  • Jessica L. Lacy,
  • Kevin H. Goslen,
  • Masha Block,
  • Jordyn Whitfield,
  • Alexander Widiapradja,
  • Scott P. Levick

Journal volume & issue
Vol. 160
p. 114365

Abstract

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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 0.05). 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.

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