Patients with diabetes develop endothelial dysfunction shortly after diabetes onset that progresses to vascular disease underlying the majority of diabetes-associated comorbidities. Increased lipid peroxidation, mitochondrial calcium overload, and mitochondrial dysfunction are characteristics of dysfunctional endothelial cells in diabetic patients. We here identified that targeting the lipid peroxidation product 12(S)-hydroxyeicosatetraenoic acid–induced [12(S)-HETE–induced] activation of the intracellularly located cation channel transient receptor potential vanilloid 1 (TRPV1) in endothelial cells is a means to causally control early-stage vascular disease in type I diabetic mice. Mice with an inducible, endothelium-specific 12/15-lipoxygenase (12/15Lo) knockout were protected similarly to TRPV1-knockout mice from type 1 diabetes–induced endothelial dysfunction and impaired vascular regeneration following arterial injury. Both 12(S)-HETE in concentrations found in diabetic patients and TRPV1 agonists triggered mitochondrial calcium influx and mitochondrial dysfunction in endothelial cells, and 12(S)-HETE effects were absent in endothelial cells from TRPV1-knockout mice. As a therapeutic consequence, we found that a peptide targeting 12(S)-HETE–induced TRPV1 interaction at the TRPV1 TRP box ameliorated diabetes-induced endothelial dysfunction and augmented vascular regeneration in diabetic mice. Our findings suggest that pharmacological targeting of increased endothelial lipid peroxidation can attenuate diabetes-induced comorbidities related to vascular disease.

Background: The transient receptor potential vanilloid 1 ( TRPV 1) mediates cellular responses to pain, heat, or noxious stimuli by calcium influx; however, the cellular localization and function of TRPV 1 in the cardiomyocyte is largely unknown. We studied whether myocardial injury is regulated by TRPV 1 and whether we could mitigate reperfusion injury by limiting the calcineurin interaction with TRPV 1. Methods and Results: In primary cardiomyocytes, confocal and electron microscopy demonstrates that TRPV 1 is localized to the mitochondria. Capsaicin, the specific TRPV 1 agonist, dose‐dependently reduced mitochondrial membrane potential and was blocked by the TRPV 1 antagonist capsazepine or the calcineurin inhibitor cyclosporine. Using in silico analysis, we discovered an interaction site for TRPV 1 with calcineurin. We synthesized a peptide, V1‐cal, to inhibit the interaction between TRPV 1 and calcineurin. In an in vivo rat myocardial infarction model, V1‐cal given just prior to reperfusion substantially mitigated myocardial infarct size compared with vehicle, capsaicin, or cyclosporine (24±3% versus 61±2%, 45±1%, and 49±2%, respectively; n=6 per group; P <0.01 versus all groups). Infarct size reduction by V1‐cal was also not seen in TRPV 1 knockout rats. Conclusions: TRPV 1 is localized at the mitochondria in cardiomyocytes and regulates mitochondrial membrane potential through an interaction with calcineurin. We developed a novel therapeutic, V1‐cal, that substantially reduces reperfusion injury by inhibiting the interaction of calcineurin with TRPV 1. These data suggest that TRPV 1 is an end‐effector of cardioprotection and that modulating the TRPV 1 protein interaction with calcineurin limits reperfusion injury.

The common aldehyde dehydrogenase 2 (ALDH2) alcohol flushing variant known asALDH2*2affects ∼8% of the world’s population. Even in heterozygous carriers, this missense variant leads to a severe loss of ALDH2 enzymatic activity and has been linked to an increased risk of coronary artery disease (CAD). Endothelial cell (EC) dysfunction plays a determining role in all stages of CAD pathogenesis, including early-onset CAD. However, the contribution ofALDH2*2to EC dysfunction and its relation to CAD are not fully understood. In a large genome-wide association study (GWAS) from Biobank Japan,ALDH2*2was found to be one of the strongest single-nucleotide polymorphisms associated with CAD. Clinical assessment of endothelial function showed that human participants carryingALDH2*2exhibited impaired vasodilation after light alcohol drinking. Using human induced pluripotent stem cell–derived ECs (iPSC-ECs) and CRISPR-Cas9–correctedALDH2*2iPSC-ECs, we modeledALDH2*2-induced EC dysfunction in vitro, demonstrating an increase in oxidative stress and inflammatory markers and a decrease in nitric oxide (NO) production and tube formation capacity, which was further exacerbated by ethanol exposure. We subsequently found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin mitigatedALDH2*2-associated EC dysfunction. Studies inALDH2*2knock-in mice further demonstrated that empagliflozin attenuatedALDH2*2-mediated vascular dysfunction in vivo. Mechanistically, empagliflozin inhibited Na⁺/H⁺-exchanger 1 (NHE-1) and activated AKT kinase and endothelial NO synthase (eNOS) pathways to ameliorateALDH2*2-induced EC dysfunction. Together, our results suggest thatALDH2*2induces EC dysfunction and that SGLT2i may potentially be used as a preventative measure against CAD forALDH2*2carriers.

The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes, such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options.