This study demonstrates that after permanent coronary artery ligation UCP3 genetic deletion is associated with larger infarct size and remodeling and higher cardiac FDG uptake in remote areas as compared to WT mice. These findings suggest that UCP3 deletion induces a metabolic shift that favored glycolytic metabolism. Moreover, the larger area of necrosis and remodeling in response to ischemia in mice leaking UCP3 confirms the cardioprotective role of this protein.
The physiological function of UCP3 is as yet unknown. It has been hypothesized that UCP3 facilitate high rates of fatty acid oxidation . UCP3 is proposed to export the potentially detrimental fatty acid anions to the intermembrane space and cytosol where they can be re-esterified for subsequent use in other pathways. This hypothesis was supported by MacLellan et al.  who observed an increased fatty acid oxidation due to augmented UCP3 expression. These results are consistent with the clinical findings of Argyropoulos et al.  who demonstrated decreased fat oxidation by indirect calorimetry in a population of Gullah-speaking African Americans with an exon six-splice donor single nucleotide polymorphism in the UCP3 gene. Decreased fat oxidation has also been documented through indirect calorimetry in UCP3−/− mice . These findings support and extend the latter and provide a potential mechanism for the detrimental effects of decreased UCP3 expression in muscle with regard to the development of lipotoxicity and insulin resistance in muscle. Seifert et al.  also indicated a role for UCP3 in the adaptation of fatty acid oxidation capacity to fasting and possibly more broadly to perturbed energy balance. In addition, Essop et al.  demonstrated a decrease of UCP3 gene expression in rat heart during hypoxia, associated with reduced fatty acid oxidation and increased reliance on glucose metabolism. These data support an overall reduction in the dependence on mitochondrial oxidative phosphorylation in the left ventricle for ATP production in response to hypobaric hypoxia. However, more recent studies have shown that UCP3 is robustly upregulated in skeletal muscle in response to hypoxia . Therefore, the effect of hypoxia on UCP3 expression is still unclear.
UCP3 is expressed in response to reperfusion after ischemia and, activating a mechanism cytoprotective antioxidant, it is capable of reducing the production of ROS and subsequent reperfusion injury [21, 22]. In rats it has been shown that the expression of UCP3 is inversely associated with infarct size, probably by activating a protective mechanism to prevent the death of cardiomyocytes in the tissue surrounding the infarcted area . An increased UCP3 expression after ischemia-reperfusion has been demonstrated also in the isolated mouse heart  and in the mouse heart in vivo . Therefore, this protein might be a potential therapeutic target for the management of cardiac ischemic disease. During myocardial ischemia, impairment of the energetic activity of the heart is associated with increased level of circulating free fatty acids . However, it has been demonstrated that muscle mitochondrial fatty acid oxidation is decreased in UCP3−/− as compared to WT mice . Thus, it is conceivable that also in the heart the reduced UCP3 levels may lead to a reduction in capacity to oxidize lipids and to in increased glucose consumption. Our data indicate that this metabolic shift is present in remote myocardium where SUV was significantly higher in UCP3−/− than in WT mice (Table 3), indicating the presence of signaling mechanisms between ischemic/necrotic and control remote tissue.
In this study we found that after permanent coronary artery ligation, infarct size and LV volume were significantly greater in UCP3−/− group compared to WT mice. Infarct size is one of the major determinants of post-ischemic cardiac remodeling and adverse outcome. To evaluate cardiac function in WT and UCP3−/− mice after myocardial infarction, transthoracic echocardiography was performed in all experimental groups. Sham-operated UCP3−/− mice showed LV fractional shortening comparable to WT. After myocardial infarction, LV fractional shortening was significantly lower compared to sham-operated mice in both WT and UCP3−/− mice. Moreover, UCP3−/− mice displayed a significant worsening in cardiac function after coronary artery ligation compared with WT.
Mailloux et al.  demonstrated that deficiency in UCP3 resulted in a metabolic shift in skeletal muscles that favored glycolytic metabolism, increased glucose uptake and increased sensitivity to oxidative challenge and these findings were confirmed by FDG uptake at PET imaging. To explore whether this metabolic shift towards glycolysis is present also in cardiac muscle, we measured glucose uptake by monitoring myocardial FDG activity in UCP3−/− and in WT mice with and without coronary artery ligation. Our results show no differences in sham-operated animals between WT and UCP3−/−. On the other hand, after myocardial infarction SUV in remote areas was higher in both WT and UCP3−/− compared to sham animals. Noteworthy, UCP3−/− mice showed the highest value of SUV and the results of two-way analysis of variance demonstrated a significant interaction between genotype and myocardial infarction. Finally, we found a significant relationship between LV volume and SUV. This finding indicates that adverse remodeling and metabolic derangement are direct related and that UCP3 deletion has an unfavorable impact on both parameters.
This study has some limitations. First, serum glucose levels were not available at time of imaging. In addition, no dynamic acquisition was performed and cardiac glucose metabolism was indexed by SUV. This approach might have been hampered by the systemic effect of UCP3 deletion on glycolytic flux in the whole body tissues. However, in non-cardiac tissue SUV was independent from UCP deletion and myocardial infarction (Table 4), indicating that blood tracer availability for myocardial uptake was not altered in UCP3−/− mice.