approfondimento - Computational Biology - # Circular RNA HMGCS1 and miR-4521 Interaction in Diabetes-Induced Vascular Endothelial Dysfunction

Circular RNA HMGCS1 Promotes Vascular Endothelial Dysfunction in Type 2 Diabetes by Sponging miR-4521

Q: How could the circHMGCS1/miR-4521/ARG1 axis be therapeutically targeted to prevent or reverse diabetes-induced vascular endothelial dysfunction?

The circHMGCS1/miR-4521/ARG1 axis presents a promising therapeutic target for preventing or reversing diabetes-induced vascular endothelial dysfunction. One approach could involve the development of specific inhibitors targeting circHMGCS1 to reduce its expression levels in diabetic endothelial cells. By inhibiting circHMGCS1, the interaction between circHMGCS1 and miR-4521 could be disrupted, allowing miR-4521 to exert its regulatory effects on downstream targets such as ARG1. Additionally, promoting the expression of miR-4521 through exogenous delivery or activation could enhance its inhibitory effects on ARG1, thereby preserving endothelial function in diabetic conditions. Targeting ARG1 directly with specific inhibitors or modulators could also be a viable strategy to counteract its detrimental effects on endothelial function in diabetes. By modulating the circHMGCS1/miR-4521/ARG1 axis, it may be possible to mitigate the progression of vascular endothelial dysfunction in diabetic individuals.

Q: What other cellular pathways or signaling mechanisms might be involved in the regulation of endothelial function by the circHMGCS1/miR-4521 interaction beyond the ARG1 axis?

Beyond the ARG1 axis, the regulation of endothelial function by the circHMGCS1/miR-4521 interaction may involve additional cellular pathways and signaling mechanisms. One potential pathway could be the modulation of endothelial nitric oxide synthase (eNOS) activity, which plays a crucial role in NO production and vascular homeostasis. The circHMGCS1/miR-4521 interaction may influence eNOS activity directly or indirectly, impacting NO levels and endothelial function. Moreover, the axis could intersect with pathways involved in oxidative stress and inflammation, both of which contribute significantly to vascular endothelial dysfunction in diabetes. By regulating the expression of key molecules involved in oxidative stress and inflammation, such as reactive oxygen species (ROS) and pro-inflammatory cytokines, the circHMGCS1/miR-4521 axis may modulate endothelial function beyond the ARG1 axis. Additionally, the axis may interact with signaling pathways related to endothelial cell proliferation, migration, and apoptosis, further influencing vascular health and integrity in diabetic conditions.

Q: Could the circHMGCS1/miR-4521 regulatory network play a role in the development of other diabetic complications beyond cardiovascular disease?

The circHMGCS1/miR-4521 regulatory network may indeed play a role in the development of other diabetic complications beyond cardiovascular disease. Given the systemic nature of diabetes and the widespread impact of dysregulated molecular pathways, the circHMGCS1/miR-4521 axis could potentially influence various diabetic complications. For instance, the axis may contribute to diabetic nephropathy by affecting renal endothelial function and promoting kidney damage. Similarly, in diabetic retinopathy, the dysregulation of the circHMGCS1/miR-4521 network could impact retinal endothelial cells, leading to vascular abnormalities and vision impairment. Furthermore, the axis may be involved in diabetic neuropathy by influencing endothelial function in peripheral nerves and contributing to nerve damage. By modulating key processes such as oxidative stress, inflammation, and endothelial dysfunction, the circHMGCS1/miR-4521 regulatory network could have far-reaching effects on various diabetic complications, highlighting its potential as a therapeutic target for mitigating the multifaceted impact of diabetes on different organ systems.

Concetti Chiave

Circular RNA HMGCS1 acts as a sponge for miR-4521, leading to increased expression of arginase 1 (ARG1) and subsequent impairment of vascular endothelial function in type 2 diabetes.

Sintesi

The study investigated the role of circular RNA HMGCS1 (circHMGCS1) and microRNA-4521 (miR-4521) in regulating vascular endothelial dysfunction (VED) associated with type 2 diabetes mellitus (T2DM).

Key highlights:

Screening of circRNAs in human umbilical vein endothelial cells (HUVECs) under high glucose and high palmitate conditions identified circHMGCS1 as significantly upregulated.
Overexpression of circHMGCS1 promoted the expression of adhesion molecules, reduced nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activity, and increased reactive oxygen species (ROS) generation in endothelial cells, thereby exacerbating VED.
miR-4521 was identified as a target of circHMGCS1 and was found to be downregulated in the diabetic endothelial environment. Overexpression of miR-4521 attenuated the adverse effects of high glucose and high palmitate on endothelial function.
Mechanistically, circHMGCS1 acted as a sponge for miR-4521, leading to increased expression of arginase 1 (ARG1), a key regulator of NO production. Inhibition of ARG1 abrogated the regulatory effects of circHMGCS1 and miR-4521 on endothelial function.
In vivo studies in diabetic mice confirmed the detrimental role of the circHMGCS1/miR-4521/ARG1 axis in diabetes-induced VED, and demonstrated that modulating this axis could be a potential therapeutic strategy.

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Statistiche

Overexpression of circHMGCS1 decreased nitric oxide (NO) content by 30-40% in endothelial cells under high glucose and high palmitate conditions.
Overexpression of circHMGCS1 inhibited endothelial nitric oxide synthase (eNOS) activity by 40-50% in endothelial cells under high glucose and high palmitate conditions.
Overexpression of circHMGCS1 increased reactive oxygen species (ROS) generation by 1.5-2 fold in endothelial cells under high glucose and high palmitate conditions.
Diabetic mice exhibited a 2-3 fold increase in arginase 1 (ARG1) expression in the thoracic aorta compared to control mice.

Citazioni

"circHMGCS1 upregulated arginase 1 (ARG1) by sponging miR-4521, leading to decrease in vascular nitric oxide secretion and inhibition of endothelial nitric oxide synthase activity, and an increase in the expression of adhesion molecules and generation of cellular reactive oxygen species, reduced vasodilation and accelerated the impairment of vascular endothelial function."
"Collectively, these findings illuminate the physiological role and interacting mechanisms of circHMGCS1 and miR-4521 in diabetes-induced cardiovascular diseases, suggesting that modulating the expression of circHMGCS1 and miR-4521 could serve as a potential strategy to prevent diabetes-associated cardiovascular diseases."

Approfondimenti chiave tratti da

Circular RNA HMGCS1 sponges miR-4521 to aggravate type 2 diabetes-induced vascular endothelial dysfunction

by Zhang,M., Du... alle www.biorxiv.org 03-06-2024

https://www.biorxiv.org/content/10.1101/2024.03.06.583717v1

Domande più approfondite

How could the circHMGCS1/miR-4521/ARG1 axis be therapeutically targeted to prevent or reverse diabetes-induced vascular endothelial dysfunction?

The circHMGCS1/miR-4521/ARG1 axis presents a promising therapeutic target for preventing or reversing diabetes-induced vascular endothelial dysfunction. One approach could involve the development of specific inhibitors targeting circHMGCS1 to reduce its expression levels in diabetic endothelial cells. By inhibiting circHMGCS1, the interaction between circHMGCS1 and miR-4521 could be disrupted, allowing miR-4521 to exert its regulatory effects on downstream targets such as ARG1. Additionally, promoting the expression of miR-4521 through exogenous delivery or activation could enhance its inhibitory effects on ARG1, thereby preserving endothelial function in diabetic conditions. Targeting ARG1 directly with specific inhibitors or modulators could also be a viable strategy to counteract its detrimental effects on endothelial function in diabetes. By modulating the circHMGCS1/miR-4521/ARG1 axis, it may be possible to mitigate the progression of vascular endothelial dysfunction in diabetic individuals.

What other cellular pathways or signaling mechanisms might be involved in the regulation of endothelial function by the circHMGCS1/miR-4521 interaction beyond the ARG1 axis?

Beyond the ARG1 axis, the regulation of endothelial function by the circHMGCS1/miR-4521 interaction may involve additional cellular pathways and signaling mechanisms. One potential pathway could be the modulation of endothelial nitric oxide synthase (eNOS) activity, which plays a crucial role in NO production and vascular homeostasis. The circHMGCS1/miR-4521 interaction may influence eNOS activity directly or indirectly, impacting NO levels and endothelial function. Moreover, the axis could intersect with pathways involved in oxidative stress and inflammation, both of which contribute significantly to vascular endothelial dysfunction in diabetes. By regulating the expression of key molecules involved in oxidative stress and inflammation, such as reactive oxygen species (ROS) and pro-inflammatory cytokines, the circHMGCS1/miR-4521 axis may modulate endothelial function beyond the ARG1 axis. Additionally, the axis may interact with signaling pathways related to endothelial cell proliferation, migration, and apoptosis, further influencing vascular health and integrity in diabetic conditions.

Could the circHMGCS1/miR-4521 regulatory network play a role in the development of other diabetic complications beyond cardiovascular disease?

The circHMGCS1/miR-4521 regulatory network may indeed play a role in the development of other diabetic complications beyond cardiovascular disease. Given the systemic nature of diabetes and the widespread impact of dysregulated molecular pathways, the circHMGCS1/miR-4521 axis could potentially influence various diabetic complications. For instance, the axis may contribute to diabetic nephropathy by affecting renal endothelial function and promoting kidney damage. Similarly, in diabetic retinopathy, the dysregulation of the circHMGCS1/miR-4521 network could impact retinal endothelial cells, leading to vascular abnormalities and vision impairment. Furthermore, the axis may be involved in diabetic neuropathy by influencing endothelial function in peripheral nerves and contributing to nerve damage. By modulating key processes such as oxidative stress, inflammation, and endothelial dysfunction, the circHMGCS1/miR-4521 regulatory network could have far-reaching effects on various diabetic complications, highlighting its potential as a therapeutic target for mitigating the multifaceted impact of diabetes on different organ systems.