Effects of Thyroid Hormone Analogue and a Leukotrienes Pathway-Blocker on Reperfusion Injury Attenuation after Heart Transplantation

Abstract

Background. Global myocardial ischemia reperfusion injury after heart transplantation is believed to impair graft function and aggravate both acute and chronic rejection episodes. Objectives. To assess the possible protective potential of MK-886 and 3,5-diiodothyropropionic acid DITPA against global myocardial ischemia reperfusion injury after heart transplantation. Materials and Methods. Adult albino rats were randomized into 6 groups as follows: group I sham group; group II, control group; groups III and IV, control vehicles (1,2); group V, MK-886 treated group. Donor rats received MK-886 30 min before transplantation, and the same dose was repeated for recipients upon reperfusion; in group VI, DITPA treated group, donors and recipients rats were pretreated with DITPA for 7 days before transplantation. Results. Both MK-886 and DITPA significantly counteract the increase in the levels of cardiac TNF-α, IL-1β, and ICAM-1 and plasma level of cTnI (P < 0.05). Morphologic analysis showed that both MK-886 and DITPA markedly improved (P < 0.05) the severity of cardiac injury in the heterotopically transplanted rats. Conclusions. The results of our study reveal that both MK-886 and DITPA may ameliorate global myocardial ischemia reperfusion injury after heart transplantation via interfering with inflammatory pathway.

MK-886 protects against cardiac ischaemia/reperfusion injury by activating proteasome-Keap1-NRF2 signalling

“…Interestingly, several 5-LOX inhibitors, such as zileuton, A-64077, and ardisiaquinone A, have been found to protect against ischaemic injury in various organs and tissues in animals [ 27 , 29 ]. Notably, MK-886 is another inhibitor of 5-LOX that has anti-inflammatory and antioxidant effects [ 30 ], and can effectively suppress artery injury, pulmonary hypertension, cardiac injury following transplantation, and renal, hepatic and intestine I/R injury by interfering with inflammation, oxidative stress and apoptosis related signalling pathways [ [31] , [32] , [33] , [34] , [35] ]. For example, MK-886 treatment significantly improves angioplasty-induced arterial injury by reducing deposition of platelets and neutrophils, vasoconstrictive response, and synthesis of leukotriene B4 [ 31 ].…”

“…For example, MK-886 treatment significantly improves angioplasty-induced arterial injury by reducing deposition of platelets and neutrophils, vasoconstrictive response, and synthesis of leukotriene B4 [ 31 ]. Administration of MK-886 can limit global cardiac I/R damage following heart transplantation through inhibiting upregulation of cardiac IL-1β, TNF-α, and ICAM-1 levels [ 32 ]. Furthermore, MK-886 treatment greatly ameliorates pulmonary hypertension triggered by angiotensin II or hypoxia in vitro and in vivo [ 33 ].…”

“…These compounds are able to limit Keap1-mediated NRF2 ubiquitination and degradation by the proteasome, which enhances NRF2-dependent upregulation of its downstream genes [ 4 , 6 , 43 ]. Previous studies have revealed that MK-866 regulates several diseases through anti-inflammatory and antioxidant activity [ [31] , [32] , [33] , [34] , [35] ] . Here, we provide a new mechanism by which MK-886 exerts antioxidant effects by increasing β5i-keap1-NRF2 signalling, leading to the amelioration of I/R-induced mitochondrial fission–fusion imbalance and heart dysfunction ( Fig.…”