Abstract
The valosin-containing protein (VCP) participates in signaling pathways essential for cell homeostasis in multiple tissues, however, its function in the heart in vivo remains unknown. Here we offer the first description of the expression, function and mechanism of action of VCP in the mammalian heart in vivo in both normal and stress conditions. By using a transgenic (TG) mouse with cardiac-specific overexpression (3.5-fold) of VCP, we demonstrate that VCP is a new and powerful mediator of cardiac protection against cell death in vivo, as evidenced by a 50% reduction of infarct size after ischemia/reperfusion versus wild type. We also identify a novel role of VCP in preserving mitochondrial respiration and in preventing the opening of mitochondrial permeability transition pore in cardiac myocytes under stress. In particular, by genetic deletion of inducible isoform of nitric oxide synthase (iNOS) from VCP TG mouse and by pharmacological inhibition of iNOS in isolated cardiac myocytes, we reveal that an increase of expression and activity of iNOS in cardiomyocytes by VCP is an essential mechanistic link of VCP-mediated preservation of mitochondrial function. These data together demonstrate that VCP may represent a novel therapeutic avenue for the prevention of myocardial ischemia.
Highlights
Further characterization was performed on the VCP TG line with a 3.5-fold overexpression (Fig. 1b), since it increased iNOS expression by 2.5-fold in protein level when compared to WT (p < 0.01 vs. WT, Fig. 1d), which best reproduces the range of iNOS expression found in the second window of preconditioning (SWOP)[16,17]
These results demonstrate that VCP is a novel agonist of iNOS-mediated mechanisms of cardioprotection against ischemia
By interacting with several sets of adaptor proteins[19], VCP is involved in a variety of cellular pathways that are essential for cell homeostasis, such as cell cycle control, transcriptional regulation, apoptosis, protein degradation, and cellular stress response[20,21,22,23]
Summary
Our previous study showed that the increase of total endogenous iNOS expression and its subsequent translocation to the mitochondria in cardiac myocytes is crucial for its effects on both mitochondrial respiration and cardioprotection[18]. Mitochondria from VCP TG mouse heart tissues showed a significant increase in oxygen consumption at the ADP-dependent state 3 under complex I stimulation compared to WT, while no significant difference was seen in oxygen consumption states 4 (upon the addition of oligomycin, a known inhibitor of the ATP synthase) (Fig. 4b).
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