Molecular mechanism of lysophosphatidic acid-induced hypertensive response

Kano, Kuniyuki; Matsumoto, Hirotaka; Inoue, Asuka; Yukiura, Hiroshi; Kanai, Motomu; Chun, Jerold; Ishii, Satoshi; Shimizu, Takao; Aoki, Junken

doi:10.1038/s41598-019-39041-4

Cited by 36 publications

(30 citation statements)

References 28 publications

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“…33 Notably, LPA species containing an unsaturated acyl chain are potent vasoconstrictors but whether cognate GPCRs for LPA (LPA 1-6 ) mediate these effects is uncertain. 31,34 We found that LPA (C18:1) constricted skeletal muscle arterioles isolated from WT but not from TRPV1-null mice confirming a selective action at TRPV1 (Fig. 5, A and B).…”

Section: Lysophosphatidic Acid Constricts Arterioles and Increases Blsupporting

confidence: 52%

“…We examined lysophosphatidic acids (LPA), a vasoconstrictor lipid species generated by platelets and atherogenic plaques (31,32), potentially activating TRPV1 (33). Notably, LPA species containing an unsaturated acyl chain are potent vasoconstrictors but whether cognate GPCRs for LPA (LPA 1-6 ) mediate these effects is uncertain (31,34). We found that LPA (C18:1) constricted skeletal muscle arterioles isolated from WT but not from TRPV1-null mice confirming a selective action at TRPV1 (Fig.…”

Section: Lysophosphatidic Acid Constricts Arterioles and Increases Blmentioning

confidence: 84%

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TRPV1 expressed throughout the arterial circulation enables inflammatory vasoconstriction

Phan

Ton

Gulyás

et al. 2020

Preprint

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The capsaicin receptor, TRPV1, is a key ion channel involved in inflammatory pain signaling.Although mainly studied in sensory nerves, there are reports of TRPV1 expression in isolated segments of the vasculature, but whether the channel localizes to vascular endothelium or smooth muscle is controversial and the distribution and functional roles of TRPV1 in arteries remain unknown. We mapped functional TRPV1 expression throughout the mouse arterial circulation. Analysis of reporter mouse lines TRPV1 PLAP-nlacZ and TRPV1-Cre:tdTomato combined with Ca 2+ imaging revealed specific localization of TRPV1 to smooth muscle of terminal arterioles in the heart, fat and skeletal muscle. Capsaicin evoked inward currents and raised intracellular Ca 2+ levels in arterial smooth muscle cells, constricted arterioles ex vivo and in vivo and increased systemic blood pressure in mice and rats. Further, capsaicin markedly and dose-dependently reduced coronary flow. Pharmacologic and/or genetic disruption of TRPV1 abolished all these effects of capsaicin as well as vasoconstriction triggered by lysophosphatidic acid, a bioactive lipid generated by platelets and atherogenic plaques. Notably, ablation of sensory nerves did not affect the responses to capsaicin revealing a vascular smooth musclerestricted signaling mechanism. Moreover, unlike in sensory nerves, TRPV1 function in arteries was resistant to activity-induced desensitization. Thus, TRPV1 activation in vascular myocytes of resistance arterioles enables a persistent depolarizing current, leading to constriction of coronary, skeletal muscle, and adipose arterioles and a sustained increase in systemic blood pressure.

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Section: Lysophosphatidic Acid Constricts Arterioles and Increases Blsupporting

confidence: 52%

Section: Lysophosphatidic Acid Constricts Arterioles and Increases Blmentioning

confidence: 84%

TRPV1 expressed throughout the arterial circulation enables inflammatory vasoconstriction

Phan

Ton

Gulyás

et al. 2020

Preprint

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“…Lysophosphatidic acid promotes transient hypertension mainly via the Gα 12/13 -coupling LPA4 receptor, one of five LPA receptors (LPA1-4 and LPA6). The ROCK inhibitor Y-27632 successfully suppresses LPA-induced hypertension, suggesting that LPA increases blood pressure via the Gα 12/13 -Rho/ROCK pathway 122 . Angiotensin II is an important factor for increasing blood pressure via AT1.…”

Section: Role Of Gα 12 In Cardiovascular Diseasementioning

confidence: 99%

Gα12/13 signaling in metabolic diseases

et al. 2020

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As the key governors of diverse physiological processes, G protein-coupled receptors (GPCRs) have drawn attention as primary targets for several diseases, including diabetes and cardiovascular disease. Heterotrimeric G proteins converge signals from~800 members of the GPCR family. Among the members of the G protein α family, the Gα 12 family members comprising Gα 12 and Gα 13 have been referred to as gep oncogenes. Gα 12/13 levels are altered in metabolic organs, including the liver and muscles, in metabolic diseases. The roles of Gα 12/13 in metabolic diseases have been investigated. In this review, we highlight findings demonstrating Gα 12/13 amplifying or dampening regulators of phenotype changes. We discuss the molecular basis of G protein biology in the context of posttranslational modifications to heterotrimeric G proteins and the cell signaling axis. We also highlight findings providing insights into the organ-specific, metabolic and pathological roles of G proteins in changes associated with specific cells, energy homeostasis, glucose metabolism, liver fibrosis and the immune and cardiovascular systems. This review summarizes the currently available knowledge on the importance of Gα 12/13 in the physiology and pathogenesis of metabolic diseases, which is presented according to the basic understanding of their metabolic actions and underlying cellular and molecular bases. GPCR-G protein pathways in metabolic diseases Metabolic syndrome has been a serious health issue in the 21st century. It is a cluster of risk factors that can lead to cardiovascular diseases, diabetes, and stroke. Insulin resistance is the major factor that induces metabolic syndrome. It has been estimated that 642 million people will have type 2 diabetes by 2040 1. The G protein-coupled receptor (GPCR) family is the largest membrane receptor family and serves as an attractive drug target. Currently, FDA-approved drugs, which account for approximately one-third of all drugs, target more than 100 GPCRs 2. The glucagon-like peptide-1 (GLP-1) receptor, a member of the glucagon receptor family of GPCRs, is a metabolic syndrome-associated drug target. GLP-1 receptor agonists are used for glycemic control in patients with type 2 diabetes mellitus 3. Because of its weight-loss effects, liraglutide (Saxenda TM) has become the first GLP-1 receptor agonist approved for the treatment of obesity 4. Many GPCRs are pivotal sensors of energy metabolism. Some GPCRs are activated by energy metabolites or substrates, such as fatty acids, nucleotides, saccharides, hydroxycarboxylic acids, and citric acid cycle intermediates 5. GPCRs activated by fatty acid-derived lipids have been proposed as antidiabetic drugs 6. For example, the beneficial effect of omega-3 fatty acids is mediated by GPR120, also known as free fatty acid receptor 4. GPR120 is an attractive therapeutic target for the treatment of type 2 diabetes. GPR120-selective agonists improve insulin resistance and chronic inflammation and are currently under investigation for possible drug development...

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“…Neurons (DIV 10, ~5 × 10 5 cells) derived from wild-type mice were treated with 10 µM LA or CLA for 24 h. Lipids were recovered with acidic methanol (pH 4.0, 200 µL) that contained 1 µM 17:0-LPC as an internal standard and stored at -80°C. LC-MS/MS analysis was performed as described previously (Kano et al, 2019) with some modifications. Briefly, LC was performed using a C18 column (CAPCELL PAK C18 (1.5 mm I.D.…”

Section: Lc-ms/ms Analysismentioning

confidence: 99%

Suppression of amyloid-β secretion from neurons bycis-9,trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid

Hata

Kikuchi

Kano

et al. 2020

Preprint

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Conjugated linoleic acid (CLA) comprises several geometric and positional isomers of the parental linoleic acid (LA). Two of the isomers, cis-9, trans-11 CLA (c9,t11 CLA) and trans-10, cis-12 CLA (t10,c12 CLA) exert various biological activities. However, the effect of CLA on generation of neurotoxic amyloid-β (Aβ) protein remains unclear. We found that c9,t11CLA significantly suppressed generation of Aβ in primary cultures of mouse neurons. CLA treatment did not affect the levels of β-site APP-cleaving enzyme 1 (BACE1), a component of active γ-secretase complex presenilin 1 amino-terminal fragment (PS1 NTF), or Aβ protein precursor (APP) in cultured neurons. BACE1 activity in lysate of neurons treated with c9,t11 CLA, but not t10,c12 CLA, decreased slightly, although c9,t11 CLA did not directly affect the activity of recombinant BACE1. Interestingly, localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, where APP is predominantly cleaved by BACE1. c9,t11 CLA and t10,c12 CLA appeared to be incorporated into membrane phospholipids, as the level of CLA-containing lysophosphatidylcholine (CLA-LPC) increased dramatically in neurons incubated with CLA. Taken together, our findings indicate that accumulation of c9,t11 CLA-LPC, but not t10,c12 CLA-LPC, in neuronal membranes suppresses amyloidogenic cleavage of APP, thereby contributing to preservation of brain neurons by suppressing neurotoxic Aβ production in aged subjects.

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Molecular mechanism of lysophosphatidic acid-induced hypertensive response

Cited by 36 publications

References 28 publications

TRPV1 expressed throughout the arterial circulation enables inflammatory vasoconstriction

TRPV1 expressed throughout the arterial circulation enables inflammatory vasoconstriction

Gα12/13 signaling in metabolic diseases

Suppression of amyloid-β secretion from neurons bycis-9,trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid

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