DITPA, a thyroid hormone analog, reduces infarct size and attenuates the inflammatory response following myocardial ischemia

J Surg Res. 2011 Dec;171(2):379-85. doi: 10.1016/j.jss.2011.04.009. Epub 2011 May 4.

Abstract

Background: Thyroid hormone can have positive effects on the cardiovascular system but its therapeutic potential is limited secondary to its adverse effects. DITPA (3,5-diiodothyroproprionic acid) is a synthetic thyroid hormone analog with positive inotropic effects similar to thyroid hormone but with minimal systemic effects. DITPA has previously been shown to reduce pathologic remodeling and improve cardiac output following myocardial infarction; however, few studies have examined the role of DITPA in determining infarct size or the early inflammatory response following myocardial ischemia. We examined the role of DITPA in the acute phase following infarction.

Materials and methods: Mice were subjected to surgical induction of myocardial infarction and were then randomized to receive daily injections of DITPA or vehicle control. After 3 d, animals were sacrificed and infarct size was determined by H and E staining. Myocardial macrophage and neutrophil accumulation was determined by immunofluorescent staining. Immunoblotting and enzyme-linked immunosorbent assay (ELISA) were used to examine the levels of intercellular adhesion molecule-1 (ICAM-1), keratinocyte-derived chemokine (KC), monocyte chemoattractant protein (MCP-1), and interleukin 6 (IL-6) in homogenates from the ischemic tissue.

Results: Compared with vehicle control, DITPA treated animals had smaller infarcts (52.1%±5.7% versus 37.3%±3.6%, P<0.05) and decreased macrophage (32±4 versus 14±1 cells/HPF, P<0.05, and neutrophil (14±2 versus 7±1 cells/HPF, P<0.05) accumulation. Myocardial ICAM-1, (2.37±0.4 versus 1.1±0.2, P<0.05), KC levels (33.32±12.4 pg/mg, versus 21.24±8.9 pg/mg, P<0.05), and IL-6 levels (112.3±78 pg/mg versus 37.3±25.9 pg/mg, P<0.05) were also reduced in the DITPA treated group, while MCP-1 levels were equivalent between groups.

Conclusions: Treatment with DITPA attenuates the acute inflammatory response and reduces myocardial infarct size. The reduction in myocardial ICAM-1, KC, and IL-6 levels in the DITPA group was associated with a decrease in macrophage and neutrophil accumulation.

MeSH terms

  • Acute Disease
  • Animals
  • Chemokine CCL2 / metabolism
  • Chemokines / metabolism
  • Diiodothyronines / pharmacology*
  • Disease Models, Animal
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interleukin-6 / metabolism
  • Macrophages / immunology
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / immunology
  • Myocardial Infarction / pathology
  • Myocardial Ischemia / drug therapy*
  • Myocardial Ischemia / immunology
  • Myocardial Ischemia / pathology
  • Myocarditis / drug therapy*
  • Myocarditis / immunology
  • Myocarditis / pathology
  • Myocardium / immunology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Neutrophils / immunology
  • Neutrophils / pathology
  • Propionates / pharmacology*

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokines
  • Diiodothyronines
  • Icam1 protein, mouse
  • Interleukin-6
  • Propionates
  • Intercellular Adhesion Molecule-1
  • keratinocyte-derived chemokines
  • 3,5-diiodothyropropionic acid