Abstract
Disruption of peripheral circadian rhyme pathways dominantly leads to metabolic disorders. Studies on circadian rhythm proteins in the heart indicated a role for Clock or Per2 in cardiac metabolism. In contrast to Clock−/−, Per2−/− mice have larger infarct sizes with deficient lactate production during myocardial ischemia. To test the hypothesis that cardiac Per2 represents an important regulator of cardiac metabolism during myocardial ischemia, we measured lactate during reperfusion in Per1−/−, Per2−/− or wildtype mice. As lactate measurements in whole blood indicated an exclusive role of Per2 in controlling lactate production during myocardial ischemia, we next performed gene array studies using various ischemia-reperfusion protocols comparing wildtype and Per2−/− mice. Surprisingly, high-throughput gene array analysis revealed dominantly lipid metabolism as the differentially regulated pathway in wildtype mice when compared to Per2−/−. In all ischemia-reperfusion protocols used, the enzyme enoyl-CoA hydratase, which is essential in fatty acid beta-oxidation, was regulated in wildtype animals only. Studies using nuclear magnet resonance imaging (NMRI) confirmed altered fatty acid populations with higher mono-unsaturated fatty acid levels in hearts from Per2−/− mice. Unexpectedly, studies on gene regulation during reperfusion revealed solely pro inflammatory genes as differentially regulated ‘Per2-genes’. Subsequent studies on inflammatory markers showed increasing IL-6 or TNFα levels during reperfusion in Per2−/− mice. In summary, these studies reveal an important role of cardiac Per2 for fatty acid metabolism and inflammation during myocardial ischemia and reperfusion, respectively.
Highlights
Epidemiological studies have shown that shift or nighttime workers have a higher incidence of cardiovascular disease [1,2,3,4,5,6,7]
Per2 but not Per1 dependent lactate production during myocardial ischemia Recent studies found a lack of lactate production in Per22/2 mice during myocardial ischemia, which was associated with larger infarct sizes after 60 minutes of ischemia
The question addressed in this study was to understand the contribution of Per2 to cardiac metabolism during myocardial ischemia and reperfusion
Summary
Epidemiological studies have shown that shift or nighttime workers have a higher incidence of cardiovascular disease [1,2,3,4,5,6,7]. The primary control of the circadian clock is located in the hypothalamic suprachiasmatic nuclei (SCN), which are used to synchronize peripheral clocks in organs and tissues [13,14]. This synchronization is accomplished through a series of tightly regulated circadian genes such as Clock, Brain and muscle Arntlike protein-1 (Bmal1)[15], Neuronal PAS domain protein 2 (Npas2), Cryptochrome (Cry1/2), and Period (Per1/2). The circadian clock in metabolism is one of the most studied areas in the field, outside of the central clock [19]
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