Gsk-3βInhibitors Mimic the Cardioprotection Mediated by Ischemic Pre- and Postconditioning in Hypertensive Rats

Abstract

The aim of this study was to examine the effects of GSK-3β inhibitors compared with PRE and POS in spontaneously hypertensive rats (SHR). Isolated hearts were submitted to the following protocols: IC: 45 min global ischemia (GI) and 1-hour reperfusion (R); PRE: a cycle of 5 min GI and 10 minutes of R prior to 45 min GI; POS: three cycles of 30 sec GI/30 sec R at the start of R. Other hearts received lithium chloride (LiCl) or indirubin-3′-monoxime,5-iodo-(IMI) as GSK-3β inhibitors. All interventions reduced the infarct size observed in IC group. The expressions of P-GSK-3β and P-Akt decreased in IC and were restored after PRE, POS, and GSK-3β inhibitors treatments. An increase of cytosolic MnSOD activity and lipid peroxidation and a decrease of GSH content observed in IC hearts were attenuated in PRE, POS, and LiCl or IMI treatments. An increase of P-GSK-3β/VDAC physical association and a partial recovery of mitochondrial permeability were also detected after interventions. These data show that, in SHR hearts, GSK-3β inhibitors mimic the cardioprotection afforded by PRE and POS and suggest that a decrease in mitochondrial permeability mediated by P-GSK-3β/VDAC interaction is a crucial event.

Enhancing Mitochondrial Health to Treat Hypertension

“…GSK-3β-induced mPTP opening has been linked to increased vulnerability to infarction in hypertensive hypertrophied hearts [62], and its inhibition improves post-ischemic recovery in pressure-overload hypertrophied hearts [63]. Similarly, treatment with GSK-3 β inhibitors attenuated mitochondrial permeability and improved antioxidant activity in hearts from salt hypertensive rats [64]. However, additional studies are needed to confirm these findings and validate GSK-3β as a target therapy in hypertension.…”

Impaired RISK-GSK3β Pathway is Responsible for Comorbidities by Suppressing the Conditioning Cardioprotection

“…Furthermore, the research team designed another study that intralipid was deprived of cardioprotection due to no capacity for upregulating the phosphorylation of Akt, ERK1/2, and their downstream target of GSK3β in the hypertrophic myocardium, but GSK3β inhibitor SB216763 failed to restore the intralipid cardioprotection (7), and it coincided with another study performed by Oei et al (65). On the contrary, some studies showed that GSK3β inhibitors imitated the cardioprotection afforded by ischemic conditioning and suggested that a decrease in mPTP by GSK3β/VDAC interaction was a crucial event (66). In addition, IpostC exerted cardioprotection in compensated hypertrophic myocardium induced by angiotensin II.…”

Food Bioactive HDAC Inhibitors in the Epigenetic Regulation of Heart Failure

“…The role for indirubin in cancer has been extensively reviewed [ 302 ]. With regard to the heart, indirubin and its derivatives protect against hyperglycemia-induced cardiac injury, aortic constriction-induced hypertrophy, I/R injury, hyperlipidemia-induced cardiac injury and diabetes-induced cardiomyopathy [ 97 , 98 , 99 , 100 , 303 , 304 ]. Cardiac protection was shown to be mediated in part through the attenuation of c-Jun-N-terminal kinase (JNK) signaling, caspase-3-directed apoptosis, and NF-ĸB expression [ 303 ].…”

“…Cardiac protection was shown to be mediated in part through the attenuation of c-Jun-N-terminal kinase (JNK) signaling, caspase-3-directed apoptosis, and NF-ĸB expression [ 303 ]. Others have reported that indirubin regulated GSK-3β signaling in order to protect cardiac function [ 97 , 98 , 99 , 100 , 304 ]. These results are interesting since class I HDACs have been shown to regulate GSK-3β signaling [ 150 ], JNK phosphorylation [ 50 ] and NF-κB activation [ 131 ].…”