12(S)-HETE mediates diabetes-induced endothelial dysfunction by activating intracellular endothelial cell TRPV1

Abstract

Conflict of interest: ERG holds a patent on "Peptide modulators of specific calcineurin protein-protein interactions" (US Application Serial No. 16/082,313) that includes the V1-cal peptide.

TRPV1 activation and internalization is part of the LPS-induced inflammation in human iPSC-derived cardiomyocytes

“…TRPV1 activation protected from atherosclerosis by eNOS production and induced angiogenesis 32 . On the other hand, TRPV1 signaling conferred the damage of cigarette smoke on cardiomyocytes 34 and mediated the endothelial dysfunction induced by 12(S)-HETE in diabetic mice 55 . It is difficult to merge these different findings into one picture.…”

TRPV1 Channel: A Noxious Signal Transducer That Affects Mitochondrial Function

“…Moreover, using confocal microscopy, it has been determined that TRPV1 displays co-localization with mitochondrial-resident proteins in primary neonatal cardiomyocytes [ 51 ]. Similarly, human parietal cells and human odontoblast-like cells exhibit positive mitochondrial immunostaining for TRPV1 [ 55 , 56 ], and recently, it has been reported that this channel is expressed in endothelial cells and found in the mitochondria [ 57 ] ( Table 1 ).…”

“…Human endothelial cells treated with 12-(S)-HETE (an arachidonic acid metabolite and a partial agonist of TRPV1 [ 30 ]) display increased mitochondrial Ca 2+ , reduced oxygen consumption rates and decreased mitochondrial membrane potentials, all of which are indicators of mitochondrial dysfunction. These indicators are also present when human endothelial cells are treated with capsaicin [ 57 ]. Interestingly, streptozotocin-induced diabetic mice exhibit increased 12-(S)-HETE levels and show impaired vascular regeneration, while in TRPV1-KO mice treated with streptozotocin, there is protection against this impairment even when their 12-(S)-HETE levels are also increased.…”

“…Interestingly, streptozotocin-induced diabetic mice exhibit increased 12-(S)-HETE levels and show impaired vascular regeneration, while in TRPV1-KO mice treated with streptozotocin, there is protection against this impairment even when their 12-(S)-HETE levels are also increased. These results suggest that TRPV1 activation by 12-(S)-HETE in diabetic mice deteriorates mitochondrial and endothelial function, favoring vascular disease [ 57 ].…”

“…Murine cardiomyocytes [51] Microglial cells [49] Heart-derived H9C2 cells [51,54] Human parietal cells [55] Human odontoblast-like cells [56] Human endothelial cells [57] Endoplasmic Reticulum DRG neurons [44][45][46][47][48] Airway smooth muscle cells [50] TRPV1-expressing cells: HEK293, COS7, Sf9, HeLa [44][45][46][47]52,58] Sarcoplasmic Reticulum Skeletal muscle cells [59,60] Golgi Complex DRG neurons [24] Microglia cells [49] Breast cancer cell lines [61] Lysosome Microglia cells [49] TRPV1 expression has also been detected in rat skeletal muscle, where this channel is mainly located in the sarcoplasmic reticulum [60], and it has been suggested to contribute to the regulation of excitation and contraction through Ca 2+ homeostasis [59]. Particularly, TRPV1 has been isolated from membrane fractions located at longitudinal sarcoplasmic reticula [59].…”