An eNAMPT-neutralizing mAb reduces post-infarct myocardial fibrosis and left ventricular dysfunction

Zhonglin Liu, Saad Sammani, Christy J. Barber, Carrie L. Kempf, Feng Li, Zhen Yang, Rosendo T. Bermudez, Sara M. Camp, Vivian Reyes Herndon, Lars R. Furenlid, Diego R. Martin, Joe G.N. Garcia

Research output: Contribution to journalArticlepeer-review

Abstract

Myocardial infarction (MI) triggers adverse ventricular remodeling (VR), cardiac fibrosis, and subsequent heart failure. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is postulated to play a significant role in VR processing via activation of the TLR4 inflammatory pathway. We hypothesized that an eNAMPT specific monoclonal antibody (mAb) could target and neutralize overexpressed eNAMPT post-MI and attenuate chronic cardiac inflammation and fibrosis. We investigated humanized ALT-100 and ALT-300 mAb with high eNAMPT-neutralizing capacity in an infarct rat model to test our hypothesis. ALT-300 was 99mTc-labeled to generate 99mTc-ALT-300 for imaging myocardial eNAMPT expression at 2 hours, 1 week, and 4 weeks post-IRI. The eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg) or saline was administered intraperitoneally at 1 hour and 24 hours post-reperfusion and twice a week for 4 weeks. Cardiac function changes were determined by echocardiography at 3 days and 4 weeks post-IRI. 99mTc-ALT-300 uptake was initially localized to the ischemic area at risk (IAR) of the left ventricle (LV) and subsequently extended to adjacent non-ischemic areas 2 hours to 4 weeks post-IRI. Radioactive uptake (%ID/g) of 99mTc-ALT-300 in the IAR increased from 1 week to 4 weeks (0.54 ± 0.16 vs. 0.78 ± 0.13, P < 0.01). Rats receiving ALT-100 mAb exhibited significantly improved myocardial histopathology and cardiac function at 4 weeks, with a significant reduction in the collagen volume fraction (%LV) compared to controls (21.5 ± 6.1% vs. 29.5 ± 9.9%, P < 0.05). Neutralization of the eNAMPT/TLR4 inflammatory cascade is a promising therapeutic strategy for MI by reducing chronic inflammation, fibrosis, and preserving cardiac function.

Original languageEnglish (US)
Article number116103
JournalBiomedicine and Pharmacotherapy
Volume170
DOIs
StatePublished - Jan 2024
Externally publishedYes

Keywords

  • Cardiac fibrosis
  • Cardioprotective effect
  • DAMP
  • Myocardial infarction
  • eNAMPT
  • mAb

ASJC Scopus subject areas

  • Pharmacology

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