Off-Target Vascular Effects of Cholesteryl Ester Transfer Protein Inhibitors Involve Redox-Sensitive and Signal Transducer and Activator of Transcription 3-Dependent Pathways

Lopes, R. A.; Neves, Karla B; Camargo, Livia L; Montezano, Augusto C.; Touyz, Rhian M.

doi:10.1124/jpet.115.230748

Cited by 10 publications

(4 citation statements)

References 31 publications

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“…Accordingly, Rios et al (43) also found that dalcetrapib has CETP-independent effects. Indeed, they demonstrated that dalcetrapib induces the secretion of aldosterone in mouse adipocytes (43) and increases the vascular contraction of rat mesenteric arteries (44). Thus, it remains possible that dalcetrapib could have an off-target effect that could be species dependent.…”

Section: Discussionmentioning

confidence: 99%

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Brodeur

Rhainds

Charpentier

et al. 2017

Journal of Lipid Research

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Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% (P < 0.01). The levels of α- and preβ-HDL were reduced by 16% (P < 0.001) and 69% (P < 0.01), resulting in a decrease of the serum cholesterol efflux capacity. CETPis modulate the plasma levels of mature and small HDL in vivo and consequently the cholesterol efflux capacity. The opposite effects of dalcetrapib in different species indicate that its impact on HDL metabolism could vary greatly according to the metabolic environment.

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Section: Discussionmentioning

confidence: 99%

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Brodeur

Rhainds

Charpentier

et al. 2017

Journal of Lipid Research

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show abstract

“…Other studies on isolated mesenteric artery smooth muscle cells in culture or isolated basilar arteries from young and old mice reveal the importance of T696 phosphorylation in mediating the vascular response to ROS (Rios et al. ; Lubomirov et al. ) and in the pathology of contractile responses of cerebral arteries from hypertensive and prediabetic rats (Abd‐Elrahman et al.…”

Section: Discussionmentioning

confidence: 99%

Augmented contractility of murine femoral arteries in a streptozotocin diabetes model is related to increased phosphorylation of MYPT1

et al. 2019

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Diabetes mellitus (DM) is a metabolic disorder with high prevalence, and a major risk factor for macro‐ and microvascular abnormalities. This study was undertaken to explore the mechanisms of hypercontractility of murine femoral arteries (FA) obtained from mice with streptozotocin (STZ)‐induced diabetes and its relation to the phosphorylation profile of the myosin phosphatase target subunit 1, MYPT1. The immunoreactivity of MYPT1 toward phospho‐MYPT1‐T696, MYPT1‐T853, or MYPT1‐S695, used as a read out for MYPT1 phosphorylation, has been studied by Western Blotting. Contractile activity of FA from control and STZ mice has been studied by wire myography. At basal conditions (no treatment), the immunoreactivity of MYPT1‐T696/T853 was ~2‐fold higher in the STZ arteries compared with controls. No changes in MYPT1‐T696/853 phosphorylation were observed after stimulation with the Thromboxan‐A2 analog, U46619. Neither basal nor U46619‐stimulated phosphorylation of MYPT1 at S695 was affected by STZ treatment. Mechanical distensibility and basal tone of FA obtained from STZ animals were similar to controls. Maximal force after treatment of FA with the contractile agonists phenylephrine (10 μmol/L) or U46619 (1 μmol/L) was augmented in the arteries of STZ mice by ~2‐ and ~1.5‐fold, respectively. In summary, our study suggests that development of a hypercontractile phenotype in murine FA in STZ diabetes is at least partially related to an increase in phosphorylation of MLCP at MYPT1‐T696/853. Interestingly, the phosphorylation at S695 site was not altered in STZ‐induced diabetes, supporting the view that S695 may serve as a sensor for mechanical activity which is not directly involved in tone regulation.

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“…Moreover, increasing HDL-C with pharmacotherapy, including cholesteryl ester transfer protein (CETP) inhibitors, did not show protective effects against CVD and mortality [ 15 , 16 , 17 , 18 ]. Among the plausible causes of adverse reactions with CETP inhibitors (torcetrapib and evacetrapib), a slight increase in blood pressure [ 19 , 20 ] and vasoactive effects [ 21 ] were observed and possibly were considered as markers of profound adverse reactions due to neuroendocrine or vasomotor effects [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Association of Serum High-Density Lipoprotein Cholesterol with High Blood Pressures at Checkup: Results of Kanagawa Investigation of Total Checkup Data from the National Database-9 (KITCHEN-9)

Nakajima

Igata

Higuchi

et al. 2021

JCM

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Background: although high-density lipoprotein has cardioprotective effects, the association between serum high-density lipoprotein cholesterol (HDL-C) and hypertension is poorly understood. Therefore, we investigated whether high and low concentrations of HDL-C are associated with high blood pressure (HBP) using a large healthcare dataset. Methods: in a community-based cross-sectional study of 1,493,152 Japanese people (830,669 men and 662,483 women) aged 40–74 years who underwent a health checkup, blood pressures automatically measured at healthcare center were investigated in nine HDL-C groups (20–110 mg/dL or over). Results: crude U-shaped relationship were observed between the nine HDL-C and blood pressures in both men and women. Logistic regression analysis showed left-to-right inverted J-shaped relationships between HDL-C and odds ratios for HBP (≥140/90 mmHg and/or pharmacotherapy), with lower limits of 90–99 mg/dL in both sexes, which were unchanged after adjusting for confounding factors. However, further adjustment for body mass index and serum triglyceride concentration revealed positive linear associations between HDL-C and HBP, although blunt U-shaped associations remained in nonalcohol drinkers. Conclusion: both low and extremely high HDL-C concentrations are associated with HBP. The former association might be dependent on excess fat mass concomitant with low HDL-C, whereas the latter association may be largely dependent on frequent alcohol consumption.

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Off-Target Vascular Effects of Cholesteryl Ester Transfer Protein Inhibitors Involve Redox-Sensitive and Signal Transducer and Activator of Transcription 3-Dependent Pathways

Cited by 10 publications

References 31 publications

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Augmented contractility of murine femoral arteries in a streptozotocin diabetes model is related to increased phosphorylation of MYPT1

Association of Serum High-Density Lipoprotein Cholesterol with High Blood Pressures at Checkup: Results of Kanagawa Investigation of Total Checkup Data from the National Database-9 (KITCHEN-9)

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