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

Abstract

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.

• Authors: Giselle C Meléndez, Kylie Kavanagh, Nazli Gharraee, Jessica L Lacy, Kevin H Goslen, Masha Block, Jordyn Whitfield, Alexander Widiapradja, Scott P Levick
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 160 Pg. 114365 (Apr 2023) ISSN: 1950-6007 [Electronic] France
• PMID: 36758315 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Substance P
• Procollagen Type I

Topics

• Female
• Mice
• Animals
• Chlorocebus aethiops
• Diabetes Mellitus, Type 2 (complications, drug therapy)
• Substance P
• Stroke Volume
• Ventricular Function, Left
• Diabetes Mellitus, Experimental (complications)
• Cardiomyopathies (drug therapy, etiology)
• Fibrosis
• Myocardium (pathology)