Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases. From the research history and milestone events related to hypoxia in cardiovascular development and diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal and spatial perspectives, encompassing the occurrence and progression of hypoxia (gradual decline in oxygen concentration), the acute and chronic manifestations of hypoxia, and the geographical characteristics of hypoxia (natural selection at high altitudes). Furthermore, hypoxia signaling pathways are associated with natural rhythms, such as diurnal and hibernation processes. In addition to innate factors and natural selection, it has been found that epigenetics, as a postnatal factor, profoundly influences the hypoxic response and progression within the cardiovascular system. Within this intricate process, interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established. Thus, it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research, including FDA-approved drugs and ongoing clinical trials, to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.

Background: Both hyperglycaemia and dendritic cells (DCs) play causative roles in atherosclerosis. However, whether they interact in atherosclerosis remains uncertain. Therefore, we examined whether high glucose could regulate the expression of scavenger receptors responsible for oxidised low-density lipoprotein (oxLDL) uptake in DCs, a critical step in atherogenesis. In addition, we investigated the impact of glucose on DC maturation regarding changes in phenotype and cytokine secretion. Methods: Immature DCs were cultured with different concentrations of glucose (5.5 mmol/L, 15 mmol/L, 30 mmol/L) in the absence or presence of N-acetylcysteine (NAC), SB203580 or Bay11-7082 for 24 hours. We used 30 mmol/L mannitol as a high-osmolarity control treatment. The expression of the scavenger receptors SR-A, CD36 and LOX-1 was determined by real-time PCR and western blot analysis. Furthermore, DCs were incubated with DiI-labelled oxLDL. The DiI-oxLDL-incorporated fraction was investigated by flow cytometry analysis. The intracellular production of ROS in DCs was measured by dichlorodihydrofluorescein (DCF) fluorescence using confocal microscopy. Finally, flow cytometry analysis was used to investigate immunophenotypic protein expression (CD83 and CD86). Supernatant cytokine measurements were used for immune function assays. Results: The incubation of DCs with glucose enhanced, in a dose-dependent manner, the gene and protein expression of SR-A, CD36 and LOX-1. This effect was partially abolished by NAC, SB203580 and Bay11-7082. Incubation of DCs with mannitol (30 mmol/L) did not enhance these scavenger receptors’ expression. High glucose upregulated the production of ROS and expression of p38 MAPK in DCs. NAC partially reversed p38 MAPK upregulation. High glucose increased the oxLDL-uptake capacity of DCs. Blockage of the scavenger receptors SR-A and CD36 reduced oxLDL uptake, but blockage of LOX-1 did not. Furthermore, high-glucose (15 mmol/L or 30 mmol/L) treatment increased CD86 and CD83 in DCs. High glucose also increased IL-6 and IL-12 secretion and decreased IL-10 secretion. Conclusion: High glucose can increase the expression of the scavenger receptors SR-A, CD36 and LOX-1, which can increase the oxLDL-uptake capacity of DCs. High glucose induces a proinflammatory cytokine profile in human DCs, leading to DC maturation. These results support the hypothesis that atherosclerosis is aggravated by hyperglycaemia-induced DC activation and oxLDL uptake.

Doxorubicin (DOX) as a chemotherapeutic agent can cause mitochondrial dysfunction and heart failure. COX5A has been described as an important regulator of mitochondrial energy metabolism. We investigate the roles of COX5A in DOX-induced cardiomyopathy and explore the underlying mechanisms. C57BL/6J mice and H9c2 cardiomyoblasts were treated with DOX, and the COX5A expression was assessed. An adeno-associated virus serum type 9 (AAV9) and lenti-virus system were used to upregulate COX5A expression. Echocardiographic parameters, morphological and histological analyses, transmission electron microscope and immunofluorescence assays were used to assess cardiac and mitochondrial function. In a human study, we found that cardiac COX5A expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to the control group. COX5A was significantly downregulated following DOX stimulation in the heart of mice and H9c2 cells. Reduced cardiac function, decreased myocardium glucose uptake, mitochondrial morphology disturbance, reduced activity of mitochondrial cytochrome c oxidase (COX) and lowered ATP content were detected after DOX stimulation in mice, which could be significantly improved by overexpression of COX5A. Overexpression of COX5A effectively protected against DOX-induced oxidative stress, mitochondrial dysfunction and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, the phosphorylation of Akt (Thr308) and Akt (Ser473) were also decreased following DOX treatment, which could be reserved by the upregulation of COX5A. Furthermore, PI3K inhibitors abrogated the protection effects of COX5A against DOX-induced cardiotoxicity in H9c2 cells. Thus, we identified that PI3K/Akt signaling was responsible for the COX5A-mediated protective role in DOX-induced cardiomyopathy. These results demonstrated the protective effect of COX5A in mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis, providing a potential therapeutic target in DOX-induced cardiomyopathy.

As an emerging discipline, panvascular diseases are a set of vascular diseases with atherosclerosis as the common pathogenic hallmark, which mostly affect vital organs like the heart, brain, kidney, and limbs. As the major responser to the most common stressor in the vasculature (hypoxia)-hypoxia-inducible factors (HIFs), and the primary regulator of pressure and oxygen delivery in the vasculature-vascular smooth muscle cells (VSMCs), their own multifaceted nature and their interactions with each other are fascinating. Abnormally active VSMCs (e.g., atherosclerosis, pulmonary hypertension) or abnormally dysfunctional VSMCs (e.g., aneurysms, vascular calcification) are associated with HIFs. These widespread systemic diseases also reflect the interdisciplinary nature of panvascular medicine. Moreover, given the comparable proliferative characteristics exhibited by VSMCs and cancer cells, and the delicate equilibrium between angiogenesis and cancer progression, there is a pressing need for more accurate modulation targets or combination approaches to bolster the effectiveness of HIF targeting therapies. Based on the aforementioned content, this review primarily focused on the significance of integrating the overall and local perspectives, as well as temporal and spatial balance, in the context of the HIF signaling pathway in VSMC-related panvascular diseases. Furthermore, the review discussed the implications of HIF-targeting drugs on panvascular disorders, while considering the trade-offs involved.

Background and Aims: Glucagon-like peptide-1 receptor agonists reduce heart failure (HF) risk in patients with diabetes or obesity. However, the extent to which this reduced risk is dependent on, or extends beyond, glucose control and weight reduction remains unclear. Methods: Two-sample cis-Mendelian randomization (MR) was used to assess causal effects of GLP-1R activation on HF risk, using glycated haemoglobin (HbA1c) reduction as a surrogate biomarker. The HF outcome was derived from a genome-wide association meta-analysis that included seven original studies and 1 665 481 participants. Primary analyses used inverse variance-weighted (IVW) and MR-robust adjusted profile score (MR-RAPS) methods. Mendelian randomization Bayesian model averaging was used to identify key mediators of the observed effects, while multivariable cis-MR with principal component generalized method of moments and network cis-MR were used to minimize the impact of confounders. Results: Genetically proxied GLP-1R activation was associated with reduced HF risk {IVW: odds ratio [OR] [95% confidence interval (CI)] .502 [.339, .743]; MR-RAPS: OR [95% CI] .492 [.320, .756]}. Mendelian randomization Bayesian model averaging identified body mass index (BMI) (marginal inclusion probability 67.2%) and Type 2 diabetes (T2D) (45.0%) as primary mediators. In multivariable cis-MR with principal component generalized method of moments, genetically predicted HbA1c levels from the GLP-1R locus remained significantly associated with HF risk after BMI adjustment, even in instances where BMI effects were non-significant [OR (95% CI) 1.663 (1.087, 2.544) at 99% variance threshold]. Network cis-MR confirmed persistent protection after adjusting for BMI [IVW: OR (95% CI) .587 (.394, .877); MR-RAPS: OR (95% CI) .577 (.375, .887)] or T2D [IVW: OR (95% CI) .508 (.343, .754); MR-RAPS: OR (95% CI) .499 (.327, .762)]. Conclusions: Glucagon-like peptide-1 receptor agonist-associated HF risk reduction is primarily mediated by BMI reduction rather than glucose control, but not fully explained by either. Residual effects after BMI and T2D adjustment suggest direct cardioprotective actions, supporting trials in non-obese, non-diabetic HF patients.