Tetrahydrobiopterin (BH4) Supplementation Prevents the Cardiorenal Effects of Diabetes in Mice by Reducing Oxidative Stress, Inflammation and Fibrosis

Novoa, Ulises; Soto, K.; Valdés, Cecilia T.; Villaseñor, Jorge; Treuer, Adriana V.; González, Daniel

doi:10.3390/biomedicines10102479

Cited by 3 publications

(1 citation statement)

References 55 publications

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“…Furthermore, the administration of BH 4 to diabetic mice ameliorated glucose intolerance and insulin resistance [114]. Recent data confirm that chronic treatment with BH 4 ameliorates the cardiorenal effects of diabetes [142].…”

Section: Uncoupled Nitric Oxide Synthase (Nos)mentioning

confidence: 82%

Hyperglycemia and Oxidative Stress: An Integral, Updated and Critical Overview of Their Metabolic Interconnections

González

Lozano

Ros‐Berruezo

et al. 2023

IJMS

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This review focuses on the multiple and reciprocal relationships that exist between oxidative stress, hyperglycemia and diabetes and related metabolic disorders. Human metabolism uses most of the consumed glucose under aerobic conditions. Oxygen is needed in the mitochondria to obtain energy, as well as for the action of microsomal oxidases and cytosolic pro-oxidant enzymes. This relentlessly generates a certain amount of reactive oxygen species (ROS). Although ROS are intracellular signals necessary for some physiological processes, their accumulation leads to oxidative stress, hyperglycemia, and progressive resistance to insulin. A cellular pro-oxidant versus an antioxidant equilibrium would regulate ROS levels, but oxidative stress, hyperglycemia, and pro-inflammatory conditions feed back to each other and the relevance of the interconnections tends to increase those conditions. Hyperglycemia promotes collateral glucose metabolism through protein kinase C, polyols and hexosamine routes. In addition, it also facilitates spontaneous glucose auto-oxidation and the formation of advanced glycation end products (AGEs), which in turn interact with their receptors (RAGE). The mentioned processes undermine cellular structures, finally giving place to a progressively greater degree of oxidative stress with further hyperglycemia, metabolic alterations, and diabetes complications. NFκB is the major transcription factor involved in the expression of most of the pro-oxidant mediators, while Nrf2 is the major transcription factor regulating the antioxidant response. FoxO is also involved in the equilibrium, but its role is controversial. This review summarizes the key factors linking the diverse glucose metabolic routes enhanced in hyperglycemia with ROS formation and vice versa, emphasizing the role of the major transcription factors involved in the desirable balance between pro-oxidant and antioxidant proteins.

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Section: Uncoupled Nitric Oxide Synthase (Nos)mentioning

confidence: 82%

Hyperglycemia and Oxidative Stress: An Integral, Updated and Critical Overview of Their Metabolic Interconnections

González

Lozano

Ros‐Berruezo

et al. 2023

IJMS

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Modulation of the nitric oxide/cGMP pathway in cardiac contraction and relaxation: Potential role in heart failure treatment

Mollace,

Scarano,

Bava

et al. 2023

Pharmacological Research

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Replicative Endothelial Cell Senescence May Lead to Endothelial Dysfunction by Increasing the BH2/BH4 Ratio Induced by Oxidative Stress, Reducing BH4 Availability, and Decreasing the Expression of eNOS

Hernandez-Navarro,

Botana,

Diez-Mata

et al. 2024

IJMS

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Vascular aging is associated with the development of cardiovascular complications, in which endothelial cell senescence (ES) may play a critical role. Nitric oxide (NO) prevents human ES through inhibition of oxidative stress, and inflammatory signaling by mechanisms yet to be elucidated. Endothelial cells undergo an irreversible growth arrest and alter their functional state after a finite number of divisions, a phenomenon called replicative senescence. We assessed the contribution of NO during replicative senescence of human aortic (HAEC) and coronary (CAEC) endothelial cells, in which accumulation of the senescence marker SA-β-Gal was quantified by β-galactosidase staining on cultured cells. We found a negative correlation in passaged cell cultures from P0 to P12, between a reduction in NO production with increased ES and the formation of reactive oxygen (ROS) and nitrogen (ONOO−) species, indicative of oxidative and nitrosative stress. The effect of ES was evidenced by reduced expression of endothelial Nitric Oxide Synthase (eNOS), Interleukin Linked Kinase (ILK), and Heat shock protein 90 (Hsp90), alongside a significant increase in the BH2/BH4 ratio, inducing the uncoupling of eNOS, favoring the production of superoxide and peroxynitrite species, and fostering an inflammatory environment, as confirmed by the levels of Cyclophilin A (CypA) and its receptor Extracellular Matrix Metalloprotease Inducer (EMMPRIN). NO prevents ES by preventing the uncoupling of eNOS, in which oxidation of BH4, which plays a key role in eNOS producing NO, may play a critical role in launching the release of free radical species, triggering an aging-related inflammatory response.

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Tetrahydrobiopterin (BH4) Supplementation Prevents the Cardiorenal Effects of Diabetes in Mice by Reducing Oxidative Stress, Inflammation and Fibrosis

Cited by 3 publications

References 55 publications

Hyperglycemia and Oxidative Stress: An Integral, Updated and Critical Overview of Their Metabolic Interconnections

Hyperglycemia and Oxidative Stress: An Integral, Updated and Critical Overview of Their Metabolic Interconnections

Modulation of the nitric oxide/cGMP pathway in cardiac contraction and relaxation: Potential role in heart failure treatment

Replicative Endothelial Cell Senescence May Lead to Endothelial Dysfunction by Increasing the BH2/BH4 Ratio Induced by Oxidative Stress, Reducing BH4 Availability, and Decreasing the Expression of eNOS

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