Defective oxidative phosphorylation (OXPHOS) and altered mitochondrial dynamics contribute to excessive mitochondrial ROS (MitoROS) production in endothelial and myocardial lesions. UCP2 plays an important role in regulating mitochondrial membrane potential (MMP), which is closely related to mitochondrial OXPHOS and dynamics. TRPV1 activation could attenuate vascular and myocardial dysfunction. It is worthwhile to determine whether TRPV1 activation by capsaicin antagonizes coronary endothelium and myocardium lesions in high-fat fed mice by alleviating altered mitochondrial OXPHOS and dynamics in a UCP2-dependent manner.Design and method:
ApoE-/-, ApoE-/-/TRPV1-/- and ApoE-/-/UCP2-/- mice were fed standard chow (ND), a high fat diet (HFD), or a high fat diet plus 0.01% capsaicin (HC) for 24 weeks. Echocardiography and electrocardiography were measured. The ratio of heart/body weight was measured and coronary arteries were dissected for vasoreactivity measurement. Aortas were used for ROS and NO evaluation and immunoblots of PKA, p-PKA, UCP2, eNOS, p-eNOS, and NADUFA9. Heart was used for hematoxylin-eosin staining, assessment of MitoROS production, OXPHOS and mitochondrial networks, and immunoblots of PKA, p-PKA, UCP2, Fis1, Drp1, Mfn2, and Opa1. HUVECs and H9C2 were incubated with ox-LDL alone or with capsaicin, iRTX, KT5720 and genipin for measurement of OXPHOS and MitoROS production, and immunoblots analysis.Results:
HFD intake impaired coronary endothelium and cardiac function. TRPV1 or UCP2 deficiency exacerbated HFD-induced disorders, which were associated with excessive MitoROS generation. TRPV1 activation increased PKA/UCP2 expression, thereby remitting mitochondrial dysfunction and inhibiting MitoROS generation. The beneficial effect of UCP2 was related to alleviated OXPHOS and MMP. Increased UCP2 contributed to the maintenance of mitochondrial networks and decreased Fis1 and Drp1 expression. Capsaicin supplementation restored coronary and cardiac function, and prolonged the lifespan of HFD-fed ApoE-/- mice.Conclusions:
Up-regulation of PKA/UCP2 signaling via TRPV1 activation protects the function of coronary arteries and heart, and prolongs the lifespan of atherosclerotic mice by ameliorating mitochondrial dysfunction.