Paradoxical effect of testosterone supplementation therapy on cardiac ischemia/reperfusion injury in aged rats

Fernando A C Seara; Raiana A Q Barbosa; Marcus V N Santos; Ainá E Domingos; Gustavo Monnerat; Adriana B Carvalho; Emerson L Olivares; José G Mill; Jose H M Nascimento; Antonio C Campos de Carvalho

doi:10.1016/j.jsbmb.2019.03.012

Paradoxical effect of testosterone supplementation therapy on cardiac ischemia/reperfusion injury in aged rats

J Steroid Biochem Mol Biol. 2019 Jul:191:105335. doi: 10.1016/j.jsbmb.2019.03.012. Epub 2019 Mar 28.

Affiliations

¹ Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Department of Physiological Sciences, Federal Rural University of Rio de Janeiro, Seropedica, RJ, Brazil. Electronic address: f.azevedo@veterinario.med.br.
² Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
³ Department of Physiological Sciences, Federal Rural University of Rio de Janeiro, Seropedica, RJ, Brazil.
⁴ Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, ES, Brazil.
⁵ Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; National Center for Structural Biology and Bioimaging, Federal University of Rio de Janeiro, RJ, Brazil.

PMID: 30930218
DOI: 10.1016/j.jsbmb.2019.03.012

Abstract

Aging is followed by numerous physiological limitations that reduce health span, particularly cardiovascular and metabolic disorders. Testosterone supplementation therapy (TST) has been widely used in the treatment of aging dysfunctions in either adult or aged patients, although recent evidence have suggested that the incidence of myocardial infarction might be increased in elderly patients. So far, though, the effects of TST in the progression of cardiac ischemia/reperfusion (IR) injury in aged hearts remain unclear. Male aged (23-24 months old) and adult (6 months old) Wistar rats were treated with placebo (Old + Placebo n = 5 / Adult + Placebo n = 5) or TST (Old + TST n = 7 / Adult + TST n = 5) for 30 days. After euthanasia, artificially-perfused isolated rat hearts were submitted to IR. Cardiac expression levels of genes encoding α and β myosin heavy chain (MHC), ryanodine receptor (RyR), brain-natriuretic peptide (BNP), sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a), glucose-regulated protein 78 kDa (GRP78), eukaryotic initiation factor 2α (eIF2α), C/EBP-homologous protein (CHOP), caspase 3 and B cell lymphoma 2 (Bcl-2) were accessed by qRT-PCR. Protein levels of CHOP, p-Akt, and p-glycogen synthase kinase 3β (p-GSK-3β) were measured by Western Blot. Compared to placebo-treated aged rats, Old + TST group exhibited increased heart weight and up-regulation of αMHC mRNA expression levels, whereas βMHC mRNA expression (p < 0.05). During reperfusion, left ventricular developed pressure, dP/dt+, dP/dt-, and cardiac contractile function index were increased in Old + TST rat hearts (p < 0.05), whereas infarct size was increased (p < 0.05) in comparison with Old + Placebo group. p-Akt levels of Old + TST rat hearts were decreased when compared to Old + Placebo group. Conversely, TST did not promote significant effects in adult rat hearts. Taken together, these findings suggest that myocardial stunning and infarct size of aged hearts were distinctly affected by TST.

Keywords: Aging; Ischemia; Myocardial infarction; Reperfusion; Testosterone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / drug effects
Animals
Dietary Supplements / adverse effects*
Disease Progression
Heart / drug effects
Heart / physiopathology
Male
Myocardial Reperfusion Injury / pathology*
Myocardial Reperfusion Injury / physiopathology
Proto-Oncogene Proteins c-akt / analysis
Rats, Wistar
Testosterone / adverse effects*
Testosterone / therapeutic use

Substances

Testosterone
Proto-Oncogene Proteins c-akt