Renin–Angiotensin System Antagonism Protects the Diabetic Heart from Ischemia/Reperfusion Injury in Variable Hyperglycemia Duration Settings by a Glucose Transporter Type 4-Mediated Pathway

Abstract

Background: Diabetes mellitus (DM) is a risk factor for cardiovascular diseases, specifically, the ischemic heart diseases (IHD). The renin–angiotensin system (RAS) affects the heart directly and indirectly. However, its role in the protection of the heart against I/R injury is not completely understood. The aim of the current study was to evaluate the efficacy of the angiotensin-converting enzyme (ACE) inhibitor and Angiotensin II receptor (AT1R) blocker or a combination thereof in protection of the heart from I/R injury. Methods: Hearts isolated from adult male Wistar rats (n = 8) were subjected to high glucose levels; acute hyperglycemia or streptozotocin (STZ)-induced diabetes were used in this study. Hearts were subjected to I/R injury, treated with Captopril, an ACE inhibitor; Losartan, an AT1R antagonist; or a combination thereof. Hemodynamics data were measured using a suitable software for that purpose. Additionally, infarct size was evaluated using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. The levels of apoptosis markers (caspase-3 and -8), antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), nitric oxide synthase (eNOS), and glucose transporter type 4 (GLUT-4) protein levels were evaluated by Western blotting. Pro-inflammatory and anti-inflammatory cytokines levels were evaluated by enzyme-linked immunosorbent assay (ELISA). Results: Captopril and Losartan alone or in combination abolished the effect of I/R injury in hearts subjected to acute hyperglycemia or STZ-induced diabetes. There was a significant (p < 0.05) recovery in hemodynamics, infarct size, and apoptosis markers following the treatment with Captopril, Losartan, or their combination. Treatment with Captopril, Losartan, or their combination significantly (p < 0.05) reduced pro-inflammatory cytokines and increased GLUT-4 protein levels. Conclusions: The blockade of the RAS system protected the diabetic heart from I/R injury. This protection followed a pathway that utilizes GLUT-4 to decrease the apoptosis markers, pro-inflammatory cytokines, and to increase the anti-inflammatory cytokines. This protection seems to employ a pathway which is not involving ERK1/2 and eNOS.

Cardioprotective and Antifibrotic Effects of Low-Dose Renin–Angiotensin–Aldosterone System Inhibitors in Type 1 Diabetic Rat Model

“…A study showed that AngII receptor type 1 agonist prevents DM-induced troponin I protein kinase C phosphorylation. It has been recently published that captopril and losartan diminish the increased level of troponin I and infarct size in STZ-diabetic rats after myocardial injury [40]. In spontaneously hypertensive rats, BNP levels were reduced in losartantreated animals [41], and in studies of acute myocardial infarction injury, ramipril and eplerenone prevented BNP elevation [42,43].…”

Effects of Apocynin, a NADPH Oxidase Inhibitor, in the Protection of the Heart from Ischemia/Reperfusion Injury

“…Additionally, a small rigid plastic tube was placed between the heart and the snare to maintain complete occlusion of the coronary artery. After ischemia, the snare was cut, and the small rigid plastic tube was removed to allow for a 30 min reperfusion, as described previously [51,52]. The animals were randomly subdivided into 9 groups (n = 8/group).…”