PPARγ-Independent Side Effects of Thiazolidinediones on Mitochondrial Redox State in Rat Isolated Hearts

Abstract

The effect of anti-diabetic thiazolidinediones (TZDs) on contributing to heart failure and cardiac ischemia/reperfusion (IR) injury is controversial. In this study we investigated the effect of select TZDs on myocardial and mitochondrial function in Brown Norway rat isolated hearts. In a first set of experiments, the TZD rosiglitazone was given acutely before global myocardial IR, and pre- and post-IR function and infarct size were assessed. In a second set of experiments, different concentrations of rosiglitazone and pioglitazone were administered in the presence or absence of the specific PPARγ antagonist GW9662, and their effects on the mitochondrial redox state were measured by online NADH and FAD autofluorescence. The administration of rosiglitazone did not significantly affect myocardial function except for transiently increasing coronary flow, but it increased IR injury compared to the control hearts. Both TZDs resulted in dose-dependent, reversible increases in mitochondrial oxidation which was not attenuated by GW9662. Taken together, these data suggest that TZDs cause excessive mitochondrial uncoupling by a PPARγ-independent mechanism. Acute rosiglitazone administration before IR was associated with enhanced cardiac injury. If translated clinically, susceptible patients on PPARγ agonists may experience enhanced myocardial IR injury by mitochondrial dysfunction.

PPARγ in Ischemia-Reperfusion Injury: Overview of the Biology and Therapy

“…However, the susceptibility of cardiomyocytes to ventricular fibrillation was increased, which was associated with ion channel dysfunction, possibly via a PPARγ-independent mechanism ( Xu et al, 2003 ). This finding was further confirmed by Riess et al They performed dose–response experiments in hearts using rosiglitazone and found a remarkable increase in mitochondrial oxidation induced by rosiglitazone, as observed by reduced NADH and increased FAD autofluorescence ( Riess et al, 2020 ). Failure of GW9662 to abolish these events indicated that increase in mitochondrial oxidation occurred in a PPARγ-independent manner.…”

“…These cellular events can damage the myocardium or increase their sensitivity to unexpected IRI. These findings may help explain the reported increase in adverse cardiac events ( Riess et al, 2020 ; Table 5 ). Together, these studies reveal that PPARγ acts on various types of tissues to confer cellular metabolism and cause deleterious side effects.…”

Mitochondria in Health and Diseases

“…The results indicate that haplogroup affiliation and the mutational spectrum of the Western Siberian LHON cohort substantially deviated from those of European populations. Another study by Riess et al [25] was focused on the adverse effects of thiazolidinediones, a class of anti-diabetic drugs, which sometimes were associated with heart failure. The latter was not clear, because these drugs activate the peroxisome proliferator-activated receptor-gamma (PPARγ), which is believed to play a key role in cardioprotection.…”

“…The latter was not clear, because these drugs activate the peroxisome proliferator-activated receptor-gamma (PPARγ), which is believed to play a key role in cardioprotection. However, Riess and coauthors [25] showed that there is another PPARγ-independent mechanism of thiazolidinedione action based on a reversible increase in mitochondrial oxidation, causing an increase in ROS production and a decrease in membrane potential. Both mechanisms may cause damage to the myocardium and have to be considered in the treatment of diabetic patients.…”

Dissecting Sex‐Related Cognition between Alzheimer’s Disease and Diabetes: From Molecular Mechanisms to Potential Therapeutic Strategies

“…Their mechanism involves stimulation of PPAR γ activity in response to insulin alterations, thus causing a drop in the serum glucose level [ 189 ]. In addition, these drugs promote neuronal Ca 2+ homeostasis in the hippocampus [ 190 ], improve IR [ 191 ], promote cholesterol homeostasis [ 192 ], and decrease cerebral inflammation via inhibition of tumor necrosis factor and interleukin-6 [ 193 ]. Such activities are postulated to improve AD patients' cognitive function and regulate A β peptide proliferation [ 194 ]; thus, it can prevent many dementia cases in upcoming years by controlling these risk factors [ 195 ].…”