The modified 6-chromanol SUL-238 protects against accelerated vascular aging in vascular smooth muscle Ercc1-deficient mice

Abstract

Introduction: Vascular aging is marked by increased mitochondrial reactive oxygen species (ROS) production, which leads to decreased nitric oxide (NO)-mediated vasodilation. Loss of NO can be partially compensated by endothelium-derived hyperpolarization (EDH), which partly relies on increased mitochondrial Ca²⁺ release to maintain vascular dilation. Thus, intervention in mitochondria may target both NO and EDH signaling to alleviate aging-related vascular dysfunction. DNA damage by mitochondrial ROS is an important cause of organismal aging. Previous work showed that local vascular Ercc1 knockout dramatically accelerates vascular aging. The aim of the study was to investigate the effect of chronic treatment with the modified 6-chromanol, SUL-238, an inhibitor of mitochondrial reverse electron flux and ROS, in a mouse model of accelerated vascular smooth muscle aging induced by DNA repair endonuclease Ercc1 knockout (SMC-KO).

Aim: The aim of the study was to investigate the effect of chronic treatment with the modified 6-chromanol, SUL-238, an inhibitor of mitochondrial reverse electron flux and ROS, in a mouse model of accelerated vascular smooth muscle aging induced by DNA repair endonuclease Ercc1 knockout (SMC-KO).

Methods: SMC-KO mice and healthy wild-type littermates received SUL-238 (90 mg/kg/day) in drinking water from 12 to 22 weeks of age. At the age of 21 weeks, arterial stiffness was measured in vivo with echography and they were euthanized at the age of 22 weeks. Ex vivo vascular function was assessed in wire myography setups and mitochondrial function of the thoracic aorta was assessed using a seahorse assay.

Results: SMC-KO mice showed reduced EDH-mediated vasodilation, elevated arterial stiffness, and increased elastin breaks at 22 weeks of age compared to their wild-type littermates. SUL-238 improved EDH, thus restoring aortic and mesenteric relaxation in SMC-KO mice. Furthermore, the number of elastin breaks was reduced and arterial stiffness normalized after treating SMC-KO mice with SUL-238. Mitochondrial respiration measured in the aorta was not different between the groups.

Conclusion: Chronic treatment with SUL-238 alleviates features of vascular aging, including decreased vasodilation and increased arterial stiffness. SUL-238 seems to have a more general effect on aging rather than involving a direct coupling between mitochondrial function and vascular signaling. SUL-238 is the first small-molecule drug reported to increase EDH after chronic treatment.

Keywords

Vascular aging / SUL-238 / mitochondria / endothelium-derived hyperpolarization (EDH)

References

[1] Collaborators GRFGlobal, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the global burden of disease study 2015.Lancet2016;388:1659-724 PMCID:PMC5388856

[2] Jouabadi SM,Golshiri K.Clinical impact and mechanisms of non-atherosclerotic vascular aging: the new kid to be blocked.Can J Cardiol2023;39:1839-58

[3] López-Otín C,Partridge L,Kroemer G.Hallmarks of aging: an expanding universe.Cell2023;186:243-78

[4] Bautista-Niño PK,Vaughan DE,Roks AJ.DNA damage: a main determinant of vascular aging.Int J Mol Sci2016;17:748 PMCID:PMC4881569

[5] Hadi HA,Al Suwaidi J.Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome.Vasc Health Risk Manag2005;1:183-98 PMCID:PMC1993955

[6] Jüttner AA,Roks AJM.Pharmacological developments in antihypertensive treatment through nitric oxide-cgmp modulation.Adv Pharmacol2022;94:57-94

[7] Golshiri K,Portilla Fernandez EC,Roks AJM.The importance of the nitric oxide-cgmp pathway in age-related cardiovascular disease: focus on phosphodiesterase-1 and soluble guanylate cyclase.Basic Clin Pharmacol Toxicol2020;127:67-80

[8] Vanhoutte PM,Feletou M.Endothelial dysfunction and vascular disease - a 30th anniversary update.Acta Physiol (Oxf)2017;219:22-96

[9] Godo S,Saito H.Disruption of physiological balance between nitric oxide and endothelium-dependent hyperpolarization impairs cardiovascular homeostasis in mice.Arterioscler Thromb Vasc Biol2016;36:97-107

[10] Behringer EJ.Impact of aging on calcium signaling and membrane potential in endothelium of resistance arteries: a role for mitochondria.J Gerontol A Biol Sci Med Sci2017;72:1627-37 PMCID:PMC5861896

[11] Kong BW,Gao Y,Leung SW.Reduced activity of skc a and na-k atpase underlies the accelerated impairment of edh-type relaxations in mesenteric arteries of aging spontaneously hypertensive rats.Pharmacol Res Perspect2015;3:e00150 PMCID:PMC4492766

[12] Chennupati R,Koehler SE.Endothelium-dependent hyperpolarization-related relaxations diminish with age in murine saphenous arteries of both sexes.Br J Pharmacol2013;169:1486-99 PMCID:PMC3724106

[13] Star BS,van Buiten A,Bouma HR.The novel compound sul-138 counteracts endothelial cell and kidney dysfunction in sepsis by preserving mitochondrial function.Int J Mol Sci2023;24:6330 PMCID:PMC10094718

[14] Hajmousa G,Brouwer LA,Henning RH.The 6-chromanol derivate sul-109 enables prolonged hypothermic storage of adipose tissue-derived stem cells.Biomaterials2017;119:43-52

[15] Lambooy SPH,Nakladal D.The novel compound sul-121 preserves endothelial function and inhibits progression of kidney damage in type 2 diabetes mellitus in mice.Sci Rep2017;7:11165 PMCID:PMC5593963

[16] Vogelaar PC,de Vrij EL.The 6-hydroxychromanol derivative sul-109 ameliorates renal injury after deep hypothermia and rewarming in rats.Nephrol Dial Transplant2018;33:2128-38

[17] Vogelaar PC,Swart DH.Towards prevention of ischemia-reperfusion kidney injury: pre-clinical evaluation of 6-chromanol derivatives and the lead compound sul-138.Eur J Pharm Sci2022;168:106033

[18] Han B,Zuo H.The novel compound sul-121 inhibits airway inflammation and hyperresponsiveness in experimental models of chronic obstructive pulmonary disease.Sci Rep2016;6:26928 PMCID:PMC4882609

[19] Durik M,van der Pluijm I.Nucleotide excision DNA repair is associated with age-related vascular dysfunction.Circulation2012;126:468-78 PMCID:PMC3430727

[20] Weeda G,de Wit J.Disruption of mouse ercc1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence.Curr Biol1997;7:427-39

[21] Yousefzadeh MJ,Bukata C.Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice.Aging Cell2020;19:e13094 PMCID:PMC7059165

[22] Ataei Ataabadi E,van der Linden J.Vascular ageing features caused by selective DNA damage in smooth muscle cell.Oxid Med Cell Longev2021;2021:2308317 PMCID:PMC8423575

[23] Golshiri K,Jüttner AA.The effects of acute and chronic selective phosphodiesterase 1 inhibition on smooth muscle cell-associated aging features.Front Pharmacol2021;12:818355 PMCID:PMC8841451

[24] Bautista-Niño PK,Rubio-Beltrán E.Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction.Clin Sci (Lond)2020;134:727-46

[25] van der Linden J,Heredia-Genestar JM.Ercc1 DNA repair deficiency results in vascular aging characterized by vsmc phenotype switching, ecm remodeling, and an increased stress response.Aging Cell2024;23:e14126 PMCID:PMC11113264

[26] Ataei Ataabadi EGK,Jüttner A.Vascular ageing features caused by selective DNA damage in smooth muscle cell.Oxid Med Cell Longev2024;2308317 PMCID:PMC8423575

[27] de Veij Mestdagh CF,Breiter JC.The hibernation-derived compound sul-138 shifts the mitochondrial proteome towards fatty acid metabolism and prevents cognitive decline and amyloid plaque formation in an alzheimer's disease mouse model.Alzheimers Res Ther2022;14:183 PMCID:PMC9733344

[28] de Waard MC,Bito V.Early exercise training normalizes myofilament function and attenuates left ventricular pump dysfunction in mice with a large myocardial infarction.Circ Res2007;100:1079-88

[29] Sharma N,Hill MA.Measurement of pulse propagation velocity, distensibility and strain in an abdominal aortic aneurysm mouse model.J Vis Exp2020;23:156 PMCID:PMC7890464

[30] Milanese C,Sepe S.DNA damage and transcription stress cause atp-mediated redesign of metabolism and potentiation of anti-oxidant buffering.Nat Commun2019;10:4887 PMCID:PMC6814737

[31] Wang M,Monticone RE.Matrix metalloproteinases promote arterial remodeling in aging, hypertension, and atherosclerosis.Hypertension2015;65:698-703 PMCID:PMC4359070

[32] Leung SW.Endothelium-dependent hyperpolarization: age, gender and blood pressure, do they matter?.Acta Physiol (Oxf)2017;219:108-23

[33] Mikhed Y,Steven S.Mitochondrial oxidative stress, mitochondrial DNA damage and their role in age-related vascular dysfunction.Int J Mol Sci2015;16:15918-53 PMCID:PMC4519931

[34] Cobb AM,Hayward R.Runx2 (runt-related transcription factor 2) links the DNA damage response to osteogenic reprogramming and apoptosis of vascular smooth muscle cells.Arterioscler Thromb Vasc Biol2021;41:1339-57

[35] Brandes RP,Félétou M.An endothelium-derived hyperpolarizing factor distinct from no and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial no synthase knockout mice.Proc Natl Acad Sci U S A2000;97:9747-52 PMCID:PMC16936

[36] Kim DE,Vermeij WP.Deficiency in the DNA repair protein ercc1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin.Aging Cell2020;19:e13072 PMCID:PMC7059167

[37] Czerwińska J,Wojtczak P.Ercc1-deficient cells and mice are hypersensitive to lipid peroxidation.Free Radic Biol Med2018;124:79-96 PMCID:PMC6098728

[38] Robinson AR,Rozgaja TA.Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging.Redox Biol2018;17:259-73 PMCID:PMC6006678

[39] Vermeij WP,Reiling E.Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice.Nature2016;537:427-31 PMCID:PMC5161687

[40] Ataei Ataabadi E,Jüttner AA.Soluble guanylate cyclase activator bay 54-6544 improves vasomotor function and survival in an accelerated ageing mouse model.Aging Cell2022;21:e13683 PMCID:PMC9470884

[41] Murphy MP,Belousov V.Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo.Nat Metab2022;4:651-62 PMCID:PMC9711940

[42] Karaś A,Pandian K.Functional deterioration of vascular mitochondrial and glycolytic capacity in the aortic rings of aged mice.Geroscience2024;46:3831-44 PMCID:PMC11226416