Lysophosphatidic acid acts on LPA1receptor to increase H2O2during flow‐induced dilation in human adipose arterioles

Chabowski, Dawid S.; Kadlec, Andrew O.; Ait‐Aissa, Karima; Hockenberry, Joseph; Pearson, Paul J.; Beyer, Andreas; Gutterman, David D.

doi:10.1111/bph.14492

Cited by 10 publications

(8 citation statements)

References 66 publications

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“…While the current study directly links the cellular localization of TERT with mt DNA damage and elevated levels of ROS, proximal and distal signaling components remain unexplored. Previous work by our lab and others indicates key pathways (eg, autophagy, 50 Sirtuin signaling, 74 PGC1α, 41 ceramide, 75 Lysophosphatidic acid, 76 acute exposure to elevated intraluminal pressure, 48 , 77 and ANG 1–7 42 ) are involved in protecting mitochondrial integrity and will require additional studies in animal models. Similar changes in gene expression presented in Table 3 show differnees between CAD and non-CAD but do not necessarily correlate or are a result of changes in TERT splice variant distribution.…”

Section: Discussionmentioning

confidence: 88%

Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment With Implications for Coronary Artery Disease

et al. 2022

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Rationale TERT, (catalytic subunit of telomerase), is linked to development of coronary artery disease (CAD); however, whether the role of nuclear vs. mitcondrial actions of TERT are involved is not determined. Dominant-negative TERT splice variants contribute to decreased mitochondrial integrity and promote elevated ROS production. We hypothesize that a decrease in mitochondrial TERT would increase mtDNA damage, promoting a pro-oxidative redox environment. The goal of this study was to define whether mitochondrial TERT is sufficient to maintain NO as the underlying mechanism of FMD by preserving mtDNA integrity. Methods and Results Immunoblots and qPCR were used to show elevated levels of splice variants α- and β-deletion TERT tissue from subjects with and without CAD. Genetic, pharmacological, and molecular tools were used to manipulate TERT localization. Isolated vessel preparations and fluorescence-based quantification of mtH2O2 and NO showed that reduction of TERT in the nucleus increased flow induced NO and decreased mtH2O2 levels, while prevention of mitochondrial import of TERT augmented pathological effects. Further elevated mtDNA damage was observed in tissue from subjects with CAD and initiation of mtDNA repair mechanisms was sufficient to restore NO mediated dilation in vessels from patients with CAD. Conclusion The work presented is the first evidence that catalytically active mitochondrial TERT, independent of its nuclear functions, plays a critical physiological role in preserving NO-mediated vasodilation and the balance of mitochondrial to nuclear TERT is fundamentally altered in states of human disease that are driven by increased expression of dominant negative splice variants.

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Section: Discussionmentioning

confidence: 88%

Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment With Implications for Coronary Artery Disease

et al. 2022

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“…Under some conditions, LPA can induce arteriolar vasodilation [27, 28]. However, LPA can also induce vascular smooth-muscle contraction [29, 30].…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Reduces Microregional Oxygen Supply/Consumption Balance after Cerebral Ischemia-Reperfusion

et al. 2020

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Background: Lysophosphatidic acid (LPA) is a small phospholipid-signaling molecule, which can alter responses to stress in the central nervous system. Objective: We hypothesized that exogenous LPA would increase the size of infarct and reduce microregional O 2 supply/consumption balance after cerebral ischemia-reperfusion. Methods: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with or without LPA (1 mg/kg, at 30, 60, and 90 min after reperfusion). Regional cerebral blood flow was determined using a C 14-iodoantipyrine autoradiographic technique. Regional small-vessel (20-60 µm in diameter) arterial and venous oxygen saturations were determined microspectrophotometrically. Results: There were no significant hemodynamic or arterial blood gas differences between groups. The control ischemic-reperfused cortex had a similar O 2 consumption to the contralateral cortex. However, microregional O 2 supply/consumption balance was significantly reduced in the ischemicreperfused cortex with many areas of low O 2 saturation (43 of 80 veins with O 2 saturation below 50%). LPA did not significantly alter cerebral blood flow, but it did significantly increase O 2 extraction and consumption of the ischemic-reperfused region. It also significantly increased the number of small veins with low O 2 saturations in the reperfused region (76 of 80 veins with O 2 saturation below 50%). This was associated with a significantly increased cortical infarct size after LPA administration (11.4 ± 0.5% control vs. 16.4 ± 0.6% LPA). Conclusion: This suggests that LPA reduces cell survival and that it is associated with an increase in the number of small microregions with reduced local oxygen balance after cerebral ischemia-reperfusion.

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“…Lipid phosphate phosphatase (LPP3), an integral plasma membrane protein, dephosphorylates and terminates outside‐in signalling of lysophosphatidic acid (LPA), a glycerol‐based lipid. Elevated levels of LPA are implicated in cardiovascular disease and are associated with vascular dysfunction (Chabowski et al., 2018; Morris & Smyth, 2013; Panchatcharam et al., 2014; Smyth et al., 2008, 2014). An increase in LPA levels has been observed with LPP3 knockdown/knockout mouse models (Busnelli et al., 2017; Chandra et al., 2018), while overexpression of LPP3 significantly reduces LPA levels (Wu et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of miR‐92a is an attractive therapeutic target and is the subject of clinical trials on wound healing (NCT03603431, NCT03494712) (Abplanalp et al., 2020). Lower expression of LPP3 driven by miR‐92a may cause LPA to accumulate and enhance signalling through LPA receptors 1 and 3, which have been implicated in microvascular dysfunction (Chabowski et al., 2018) and atherosclerosis (Smyth et al., 2014). Together, these findings demonstrate that LPP3 may play an integral role in maintaining normal vascular function by regulating LPA signalling.…”

Section: Introductionmentioning

confidence: 99%

Lipid phosphate phosphatase 3 maintains NO‐mediated flow‐mediated dilatation in human adipose resistance arterioles

Chabowski

Hughes

Hockenberry

et al. 2023

The Journal of Physiology

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Microvascular dysfunction predicts adverse cardiovascular events despite absence of large vessel disease. A shift in the mediator of flow‐mediated dilatation (FMD) from nitric oxide (NO) to mitochondrial‐derived hydrogen peroxide (H2O2) occurs in arterioles from patients with coronary artery disease (CAD). The underlying mechanisms governing this shift are not completely defined. Lipid phosphate phosphatase 3 (LPP3) is a transmembrane protein that dephosphorylates lysophosphatidic acid, a bioactive lipid, causing a receptor‐mediated increase in reactive oxygen species. A single nucleotide loss‐of‐function polymorphism in the gene coding for LPP3 (rs17114036) is associated with elevated risk for CAD, independent of traditional risk factors. LPP3 is suppressed by miR‐92a, which is elevated in the circulation of patients with CAD. Repression of LPP3 increases vascular inflammation and atherosclerosis in animal models. We investigated the role of LPP3 and miR‐92a as a mechanism for microvascular dysfunction in CAD. We hypothesized that modulation of LPP3 is critically involved in the disease‐associated shift in mediator of FMD. LPP3 protein expression was reduced in left ventricle tissue from CAD relative to non‐CAD patients (P = 0.004), with mRNA expression unchanged (P = 0.96). Reducing LPP3 expression (non‐CAD) caused a shift from NO to H2O2 (% maximal dilatation: Control 78.1 ± 11.4% vs. Peg‐Cat 30.0 ± 11.2%; P < 0.0001). miR‐92a is elevated in CAD arterioles (fold change: 1.9 ± 0.01 P = 0.04), while inhibition of miR‐92a restored NO‐mediated FMD (CAD), and enhancing miR‐92a expression (non‐CAD) elicited H2O2‐mediated dilatation (P < 0.0001). Our data suggests LPP3 is crucial in the disease‐associated switch in the mediator of FMD. Key points Lipid phosphate phosphatase 3 (LPP3) expression is reduced in heart tissue patients with coronary artery disease (CAD). Loss of LPP3 in CAD is associated with an increase in the LPP3 inhibitor, miR‐92a. Inhibition of LPP3 in the microvasculature of healthy patients mimics the CAD flow‐mediated dilatation (FMD) phenotype. Inhibition of miR‐92a restores nitric oxide‐mediated FMD in the microvasculature of CAD patients.

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Lysophosphatidic acid acts on LPA₁receptor to increase H₂O₂during flow‐induced dilation in human adipose arterioles

Abstract: These findings suggest an LPA receptor-dependent pathway by which LPA increases arteriolar release of mtH O as a mediator of FMD.

Cited by 10 publications

References 66 publications

Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment With Implications for Coronary Artery Disease

Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment With Implications for Coronary Artery Disease

Lysophosphatidic Acid Reduces Microregional Oxygen Supply/Consumption Balance after Cerebral Ischemia-Reperfusion

Lipid phosphate phosphatase 3 maintains NO‐mediated flow‐mediated dilatation in human adipose resistance arterioles

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