Selective Insulin-like Growth Factor Resistance Associated with Heart Hemorrhages and Poor Prognosis in a Novel Preclinical Model of the Hematopoietic Acute Radiation Syndrome

Radiat Res. 2018 Aug;190(2):164-175. doi: 10.1667/RR14993.1. Epub 2018 May 29.

Abstract

Although bone marrow aplasia has been considered for the past decades as the major contributor of radiation-induced blood disorders, cytopenias alone are insufficient to explain differences in the prevalence of bleeding. In this study, the minipig was used as a novel preclinical model of hematopoietic acute radiation syndrome to assess if factors other than platelet counts correlated with bleeding and survival. We sought to determine whether radiation affected the insulin-like growth factor-1 (IGF-1) pathway, a growth hormone with cardiovascular and radioprotective features. Gottingen and Sinclair minipigs were exposed to ionizing radiation at hematopoietic doses. The smaller Gottingen minipig strain was more sensitive to radiation; differences in IGF-1 levels were minimal, suggesting that increased sensitivity could depend on weak response to the hormone. Radiation caused IGF-1 selective resistance by inhibiting the anti-inflammatory anti-oxidative stress IRS/PI3K/Akt but not the pro-inflammatory MAPK kinase pathway, shifting IGF-1 signaling towards a pro-oxidant, pro-inflammatory environment. Selective IGF-1 resistance associated with hemorrhages in the heart, poor prognosis, increase in C-reactive protein and NADPH oxidase 2, uncoupling of endothelial nitric oxide synthase, inhibition of nitric oxide (NO) synthesis and imbalance between the vasodilator NO and the vasoconstrictor endothelin-1 molecules. Selective IGF-1 resistance is a novel mechanism of radiation injury, associated with a vicious cycle amplifying reactive oxygen species-induced damage, inflammation and endothelial dysfunction. In the presence of thrombocytopenia, selective inhibition of IGF-1 cardioprotective function may contribute to the development of hemostatic disorders. This finding may be particularly relevant for individuals with low IGF-1 activity, such as the elderly or those with cardiometabolic dysfunctions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Radiation Syndrome / diagnosis*
  • Acute Radiation Syndrome / metabolism*
  • Acute Radiation Syndrome / pathology
  • Angiotensin II / metabolism
  • Animals
  • Biopterins / analogs & derivatives
  • Biopterins / metabolism
  • C-Reactive Protein / metabolism
  • Disease Models, Animal
  • Heart / radiation effects*
  • Hematopoietic System / radiation effects*
  • Hemorrhage / diagnosis*
  • Hemorrhage / etiology*
  • Hemorrhage / metabolism
  • Hemorrhage / pathology
  • Insulin-Like Growth Factor I / metabolism*
  • Male
  • Nitric Oxide Synthase Type III / metabolism
  • Prognosis
  • Radiation Tolerance
  • Signal Transduction / radiation effects
  • Swine
  • Swine, Miniature

Substances

  • Angiotensin II
  • Biopterins
  • Insulin-Like Growth Factor I
  • C-Reactive Protein
  • Nitric Oxide Synthase Type III
  • sapropterin