**PPA R γ-Independent Side Effects of Thiazolidinediones on Mitochondrial Redox State in Rat Isolated Hearts**

#### **Matthias L. Riess 1,2,3,\*, Reem Elorbany 4, Dorothee Weihrauch 5, David F. Stowe 5,6,7,8 and Amadou K.S. Camara 5,6**


Received: 16 December 2019; Accepted: 17 January 2020; Published: 20 January 2020

**Abstract:** The e ffect of anti-diabetic thiazolidinediones (TZDs) on contributing to heart failure and cardiac ischemia/reperfusion (IR) injury is controversial. In this study we investigated the e ffect 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, di fferent concentrations of rosiglitazone and pioglitazone were administered in the presence or absence of the specific PPARγ antagonist GW9662, and their e ffects on the mitochondrial redox state were measured by online NADH and FAD autofluorescence. The administration of rosiglitazone did not significantly a ffect 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 sugges<sup>t</sup> 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.

**Keywords:** GW9662; ischemia reperfusion injury; Langendor ff; myocardial; pioglitazone; redox state; rosiglitazone; TZD; uncoupling
