Vascular depression and cardiovascular complications of type 2 diabetes

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Vascular depression and cardiovascular complications of type 2 diabetes

Kostrikova U.A., Myakinkova L.O., Pustovoit G.L., Yarmola T.I., Poltava State Medical University

The paper highlights the scientific foundations that link the two-way pathophysiological mechanisms of the development of depression with the worsening of type 2 diabetes and coronary heart disease, congestive heart failure, and an increase in cardiovascular risk. The term "vascular depression"is defined as associated with organic changes in the brain characteristic of cerebrovascular diseases and type 2 diabetes; according to magnetic resonance imaging, they are identified as hyperintensity of the white matter of the brain. The development of white matter hyperintensity is facilitated by vascular dysregulation, transient ischemia, inflammation, and ischemic damage. Disturbances in the regulation of vascular tone that occur during the development of depressive states and their connection with somatic pathology, a decrease in cerebral blood flow, and the appearance of affective and cognitive symptoms are described.

The importance of increased arterial stiffness and endothelial dysfunction in the development of depression is highlighted. The regulatory mechanisms of the influence of glucose, nitric oxide, pro-inflammatory cytokines, arachidonic acid, and eicosanoids on vascular regulation and their disturbances in patients with depression and type 2 diabetes are described. The features of astrocytic and neuronal homeostasis of the brain, the neurotoxicity of carbohydrate metabolism disorders and glutamate metabolism, their importance in the violation of vasoactive reactions, and the depression development in patients with type 2 diabetes are indicated. The mechanisms of neuro-endocrine, metabolic and enzymatic vascular regulation, their features in patients with type 2 diabetes and depression, their influence on the course, the prognosis of the disease and cardiovascular risk are considered.

Key words: depression, diabetes mellitus, vascular endothelial regulation, cardiovascular diseases, vasoactive substances.

Introduction

According to data published on the WHO website, approximately 280 million people worldwide suffer from depression [1]. Depression is the world's leading cause of disability and a significant contributor to the global burden of disease [2]. It has acted as an independent risk factor for developing cardiovascular, cerebrovascular, and neurodegenerative diseases in the last ten years. On the other hand, vascular and neurodegenerative diseases of the brain can cause depression [3].

"Vascular depression" as a concept was first mentioned in the works of G.S. Alexopoulos and co-authors in 1997 [4]. Their hypothesis suggested that "...cerebrovascular disease may cause, accelerate, or maintain some depressive syndromes." The authors proposed a working definition based on the presence of vascular risk factors. The clinical picture of "vascular depression", according to this definition, was characterized by cognitive deficits, psychomotor retardation, lack of understanding and disability, which was disproportionate to the severity of the depressive disorder [5]. Also confirmed is the fact that depression is a chronic mood disorder widespread in the vascular pathology of the brain; its severe course is more common in people with vascular lesions than in those suffering from Alzheimer's disease [6].

Depression and anxiety are two common mood changes among patients with cardiovascular disease associated with poor prognosis and increased cardiovascular risk [7]. Depressive disorder is increasingly recognized as an independent risk factor for developing and associated with a worse course of coronary heart disease (CHD). Numerous studies have demonstrated a direct relationship between depression and increased mortality or non-fatal cardiovascular events by more than two times in this group of patients. Furthermore, it was established that mild depression and its moderate and severe forms could be risk factors for re-hospitalization for vascular and non-vascular reasons [8-11]. At the same time, the prevalence of depression, defined as major depressive disorder or an exacerbation of its symptoms based on questionnaires, is almost twice as high among adults with diabetes compared with those without this chronic metabolic condition. Type 2 diabetes mellitus (T2DM) is a pathology that causes significant morbidity and mortality and is associated with considerable treatment costs [12].

Analysis of the bidirectional relationship between depression and macrovascular and microvascular complications of diabetes revealed that depression increases the risk of myocardial infarction, coronary heart disease, and congestive heart failure associated with T2DM [13]. A cohort study of 192,685 patients with and without diabetes and depression showed that the risk of macrovascular complications, such as acute coronary syndrome and stroke, was 1.35 times higher in patients with diabetes and depression than in nondepressed patients [14]. T2DM with comorbid depression increases the risk of cardiovascular diseases and the probability of fatal events. Depression is a common disorder among asymptomatic elderly patients with T2DM. In a study of 274 patients with asymptomatic T2DM, comorbid depression increased the risk of heart failure by 2.5 times [15]. In addition, depression can affect overall mortality in patients with prediabetes, significantly increasing its probability [16]. Since depression is an adverse factor influencing the course of T2DM and CHD, its impact on the combined course of these diseases remains to be determined in the future.

The aim of the study

Summarize existing scientific data characterizing the impact of depression on the course of type 2 diabetes, coronary heart disease, and vascular endothelial dysfunction.

Object and research methods. Analysis of modern scientific experimental and clinical research.

Research results and their discussion

A distinctive feature of vascular depression determined by magnetic resonance imaging (MRI) is the presence of lesions of the brain's white matter, identified as its hyperintensity. White matter hyperintensities (WMHI) are particularly associated with cerebrovascular risk factors, including diabetes, heart disease, and hypertension [17-19]. WMHI is more significant in volume in patients with type 2 diabetes and is associated with pronounced cognitive impairment and depressive states [20]. Vascular dysregulation contributes to the development of WMHI, as it is susceptible to transient ischemia, and many of the described cases are of ischemic origin [21, 22]. In addition, it was noted that pathological processes accompanied by arterial hypertension and changes in blood pressure are directly associated with depressive states [23, 24] and also contribute to the development of WMHI [25], especially when there is a violation of cerebral vasomotor reactivity and a change in the processes of the tone autoregulation of cerebral vessels [26, 27]. "Vascular depression" as a potential diagnostic entity may not be limited to patients of older age groups. Individuals with an early onset of this pathological condition have an increased vascular risk, as it is associated with the development of vasopa- thies and stroke [28].

Neuroimaging and neuropathological studies demonstrate that WMHI reflects a comprehensive process range, including perivascular demyelination, arteriosclerosis, ischemia, gliosis, or partial loss of myelin and axons by nerve cells [22], and deep WMHI directly correlates with ischemic processes in the brain [29].

Processes associated with various diseases contribute to developing pro-inflammatory conditions in the human body [30]. It was found that the activation of the immune system can be a characteristic feature of depressive disorders [31] and accelerate the development and manifestations of depressive symptoms [32]. Therefore, there is an assumption that immune dysregulation can contribute to the development of affective disorders and the appearance of cognitive disorders in depression. Even without the manifestation of diseases, patients with depression have an increased level of pro-inflammatory [33] and a decreased level of anti-inflammatory cytokines [34]. Pro- inflammatory processes also contribute to accelerated neurodegeneration. An increase in peripheral markers of inflammation is associated with an increased risk of dementia, and increased cytokine levels are associated with depressive symptoms in humans, with elevated IL-6 most likely, but also IL-1P, IL-8, and TNFa [ 35]. Chronic, low-intensity inflammation is a common feature of CHD and diabetes. In both conditions, activation of the release of neutrophil extracellular traps is observed, which will induce macrophages to release cytokines IL-1P and IL-18, and this process is enhanced in chronic aseptic inflammation [36].

Dysregulation of vascular tone is common in depressive disorders [37]. Decreased blood flow in the brain can disrupt its regional functions, contributing to affective and cognitive symptoms. Regional cerebral metabolic activity is closely correlated with blood flow, which is regulated by local interactions between neurons, glia, and the vasculature. In addition, cerebral blood flow is influenced by systemic hemodynamics and cerebrovascular autoregulation when cerebral arteries contract or dilate in response to changes in pressure. These processes interact to maintain stable perfusion, but they are disturbed in the context of the development of vascular diseases: hypertension, diabetes, and atherosclerosis lead to intimal proliferation, hypertrophy of the vascular wall, a decrease in the diameter of the arteries lumen, a reduction in their distensibility and dysfunction of endothelial cells.

Vascular intima growth, increased arterial stiffness, and endothelial dysfunction are changes expressed in depression [38]. Vascular pathology decreases the volumetric velocity of blood flow and vasomotor reactivity, [39] negatively affecting cerebral blood flow. A mild reduction in cerebral circulation can impair cognitive and affective processes, whereas a more considerable decrease in the context of autoregulatory deficits can cause ischemic damage. The subcortical white matter is susceptible to these changes because terminal arterioles supply it with limited collateral blood flow [40].

To understand the possible mechanisms of vascular depression in patients with coronary heart disease and diabetes, it is necessary to remember that the brain is one of the most active metabolic organs of the human body. The oxygen demand of the brain tissue is more than 20% of the total body. Thus, adequate cerebral circulation must meet the oxygen demand of the brain tissue. Regulation of cerebral circulation is based on the complex interaction of cardiovascular, respiratory and nervous physiology. Typically, these systems maintain adequate cerebral circulation by modulating hydrodynamic parameters (cerebral vascular resistance, arterial, intracranial, and venous pressure) [41].

Vasoactive agents released from the brain's parenchyma can affect cells located in the vascular system, causing an appropriate vascular response. Different types of cells are found at different levels of the vascular tree. Smooth muscle cells of the vascular wall are susceptible to the action of vasoactive substances: both vasoconstrictors and vasodilators. Synaptic transmission is essential to neurovascular communication by producing vasoactive metabolites such as arachidonic acid derivatives, lactate, adenosine, and nitric oxide. The site of synthesis of these metabolites is the neuron, astrocyte, and smooth muscle cells. Neurons and astrocytes are located near the neuronal synapse, where the signal is initiated, and the smooth muscle cells of the microcirculatory regulatory system ensure neurovascular connection [42]. Regardless of the place of formation, the point of the activity is the smooth muscle fibres surrounding arterioles and capillaries [43].

Nitric oxide (NO) is the primary mediator regulating the vascular brain tone [42, 44]. Nitric oxide synthase (NOS) has several isoforms. Endothelial NOS (eNOS) is an isoform found in the brain's blood vessels, particularly in the endothelium [45]. Neuronal NOS (nNOS) is the isoform found in neurons. A third isoform, inducible NOS (iNOS), has been found in brain tissue. Blockade of nNOS caused the most significant reduction (by 64%) in the neurovascular response. Recent human studies using a non-selective inhibitor of nitric oxide synthase confirmed the importance of its release for the realization of the phenomenon of functional hyperemia [46].

Nitric oxide is a vasodilator that exerts its effect through cGMP-dependent hyperpolarization of vascular smooth muscles due to the opening of potassium channels. Although it increases cGMP in vascular smooth muscle cells, this role is not observed in pericytes. During the activation of neurons, the relaxation of pericytes surrounding the capillaries is considered to cause a significant increase in blood flow [47]. In capillary pericytes, nitric oxide has an indirect vasodilatory effect by suppressing the production of the metabolite of arachi- donic acid - 20-hydroxyeicosatetraenoic acid, which is synthesized through cytochrome P450 (CYP450), which inhibits calcium-activated potassium channels; this process leads to depolarization and vasoconstriction [48]. In patients with diabetes, there is a constant significant activation of protein kinase C under the influence of substantial concentrations of glucose in the blood, which leads to a decrease in the synthesis of nitric oxide in vascular smooth muscle cells [49] and suppresses the expression of endothelial nitric oxide synthase stimulated by insulin, [50] and also induces the expression of endothelial growth factor in vascular smooth muscle cells. In addition, the reduced activity of nitric oxide in patients with diabetes may be caused by a violation of its production due to impaired signal transmission, a deficiency of NO-synthase substrate, or a decrease in the availability of cofactors necessary for the optimal functioning of this enzyme. Furthermore, the activation of peroxidation in diabetes initiates the rapid inactivation of nitric oxide by reactive oxygen species with the formation of peroxynitrite, which has a toxic, damaging effect on biological molecules [51].

The brain is enriched with polyunsaturated fatty acids, especially arachidonic acid [52]. Three central enzyme systems involved in metabolism have been identified: cyclooxygenase (COX), lipoxygenase (LOX) and epoxygenase (EPOX). Arachidonic acid is a substrate for the enzyme mentioned above systems [53]. Different concentrations of enzymes and their isoforms in different places determine the overall effect on cerebral blood flow. Of the many metabolites produced by COX, the vasodilators prostacyclin (PGI2) and prostaglandin E2 (PGE2) and epoxyeicosatrienoic acids (EET) predominate in normal endothelium.

Eicosanoids are a group of vasoactive derivatives of arachidonic acid. They are endothelial hyperpolariz- ing factors that protect against ischemic tissue damage and have an anti-inflammatory effect [54]. Vasodilation in response to EET activity has been observed in several organs, including the heart, brain, kidney, skeletal muscle, and intestine [55]. All active substances of the cyclooxygenase pathway (prostaglandin H2 and its followers' prostaglandin F2a and thromboxane A2) are essential in developing pathological processes. PGE2 affects capillary pericytes through the EP4 receptor [47, 56]. A biphasic, dose-dependent action via EP4 and EP1 receptors is observed at low and high concentrations. Binding to EP1 occurs in high concentrations and causes vasospasm. EETs can also function inside the cell by binding to ion channels and activating them by signalling proteins or transcription factors. Experimental data confirm the intracellular mechanism of action, which consists in the fact that EETs are embedded in phospholipids of the cell membrane, bind to fatty acid-binding proteins, and peroxisome proliferator-activated receptor (PPAR) у [57].

EETs have been shown to promote blood circulation at the capillary level and act on the EP4 receptor. Two regioisomeric EETs produced by endothelial cells dilate blood vessels by exciting large conductance calcium- activated K+ (K-Ca) channels on vascular smooth muscle cells, [58] leading to K+ efflux from smooth muscle cells and subsequent membrane hyperpolarization. In addition, there is evidence that EETs reduce inflammation. The anti-inflammatory effects of EET include the reduction of human polymorphonuclear leukocyte aggregation and leukocyte adhesion to endothelial cells [59] and attenuating IL-ip-induced fever. While free (released) EETs can be substrates for partial p-oxidation or chain elongation, their main catabolic pathway is rapid hydrolysis to the corresponding dihydryl forms (DHET) by soluble epoxide hydrolase (sEH), a cytosolic enzyme. sEH is mainly expressed in astrocytes [60], and studies suggest that polyunsaturated fatty acid metabolism may be involved in the pathophysiology of depressive disorders [61, 62]. The conversion of EET epoxides to the corresponding diols by soluble epoxide hydrolases is responsible for the reduction of EET levels and thus reduces their protective properties [63]. Therefore, inhibition of this enzyme may be a target for treating cardiovascular diseases and brain disorders, which would prevent the conversion of EET to DHET and improve dilator activity in human blood vessels [64].

EET and soluble epoxide hydrolase blockers (sEHIs) counteract the vasoconstrictor activity of the prohypertensive hormones endothelin-1 and angiotensin II [65]. A recent clinical study found higher concentrations of sEH-related oxylipins in individuals with white matter hyperintensities on MRI, which were also associated with impaired executive function [66]. Subsequently, it was established that sEH metabolites were specifically related to the speed of psychomotor information processing [67]. Overall, these results suggest that elevated sEH activity may be a marker and factor in cerebral small vessel disease.

Dysfunction of the CYP450-sEH pathway has been reported in clinical trials of seasonal depression, major depression without T2DM, and significant depression with T2DM [68, 69, 70]. Higher levels of sEH activity were found in depressed patients with type 2 diabetes compared to non-depressed T2DM patients matched for glycated haemoglobin (HbAlc), age, and body mass index, whereas epoxides were generally lower. A large amount of literature has linked depression to inflammatory cytokine concentrations in individuals with and without type 2 DM [71]; however, these relationships are highly heterogeneous. In carefully selected patients with type 2 DM, serum IL-6, a classical marker of inflammation, did not differ between depressed and non-de- pressed patients and was not associated with depressive symptoms, whereas CYP450-sEH metabolites showed a robust association that suggests that systemic depression may be related to a poor pro-soluble lipid response rather than inflammation per se [70, 72]. In animal experiments, chronic stress increased the expression of sEH in the liver of mice and caused depressive phenotypes. In contrast, genetic deletion of hepatic Ephx2 (which encodes the sEH enzyme) resulted in resistance to developing depressive symptoms [73]. Elevated sEH protein levels have also been reported in studies of postmortem brain and liver samples from depressed patients, where quantitative brain and liver sEH values are positively correlated, suggesting a possible disruption of communication between these organs as a result of metabolic changes in type 2 diabetes [74].

Astrocytes support almost all aspects of brain function, including ion and neurotransmitter homeostasis, neural circuit formation, synaptic plasticity and function, and neurovascular communication [75]. Available data confirm that the dysfunction of astrocytes in frontolimbic regions is involved in the pathophysiology of depressive disorders [76]. In addition, astrocytes release adenosine ATP, specifically adenosine, d-serine, and glutamate, which are vital for the induction of depressive symptoms and the strength of antidepressant responses [77].

Increasing evidence suggests that the frontolimbic zone is an affected region in the pathophysiology of depression [78]. A sustained increase in the excitability of this brain region is sufficient to induce anhedonia, the main symptom of depression [79]. The frontolimbic area is essential for behavioural adaptation in response to stress. Based on previous studies and data, it was hypothesized that EET signalling in astrocytes of this region might play an important role in behavioural adaptation in response to stress. Glutamatergic neurotransmission occurs mainly within the tripartite synapse, including astrocyte processes, presynaptic axon terminals, and post- synaptic elements [80]. Acute exposure to stress rapidly increases extracellular glutamate, which stimulates the release of ATP from astrocytes. This extracellular ATP is rapidly cleaved to adenosine, which activates presynaptic A1 or P2Y receptors to inhibit neuronal activity [81]. Such feedback regulation probably provides behavioural adaptation, which leads to a correct response to changes in the surrounding environment. There is evidence that acute stress transiently increases glutamate release before ATP release [82], and data showing that A1 receptors mediate the antidepressant effect of sleep deprivation [83]. Chronic stress has been shown to induce higher levels of sEH oligomerization, which disrupts EET signalling. It thus decreases ATP release from astrocytes in response, ultimately leading to increased excitability of the frontolimbic region, which may cause anhedonia in depression [79, 84]. Hyperglycemia in diabetes can dramatically increase the glucose level in brain cells, leading to their damage, a phenomenon called glucose neurotoxicity [85]. Astrocytes respond to all forms of CNS injury by a process commonly referred to as reactive astrogliosis. It is not a simple "all-or-nothing" phenomenon but rather a finely graded continuum of changes that occur depending on the context and are regulated by certain signalling events. These changes range from reversible changes in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure to long-term scarring with the remodelling of tissue structure [86]. They can also be the reason for the development of diabetic cerebral neuropathy. High glucose increases the production of reactive oxygen species, the expression of inflammatory cytokines, and cell apoptosis in primary astrocytes [87]. Anatomically, glucose can be transported mainly in the astrocyte, as it is a component of the blood-brain barrier (BBB) [88].

Astrocytes have processes that, on the one hand, are in contact with blood vessels, and on the other, with neuronal axons (in nodes of Ranvier) and synapses, aptly located to absorb glucose from blood vessels and supply energy with metabolites to various nerve cells. The utilization of astrocytic glycogen can support neuronal activity during hypoglycemia and periods of high activity [89]. Astrocytes have a higher glucose metabolism than neurons, and activation of the somatosensory cortex increases its absorption mainly by astrocytes [90]. High glucose irreversibly suppresses astrocyte proliferation, an essential component of reactive gliosis in response to various brain injuries [91], while diabetes suppresses activation of the somatosensory cortex after perfusion [92]. Inhibition of astrogliosis in diabetes can be explained by the inhibitory effect of high glucose on astrocytic proliferation. High glucose increases glycolysis and increases lactate production and ATP content in astrocytes. Recent studies have shown that the astrocyte-neuron lactate pathway supplies substrate for the latter's metabolism [93]. Lactate can be an essential source of energy for neurons; at the same time, its excessive level can cause their damage [94].

The exact mechanism by which depression increases the risk of cardiovascular disease in type 2 diabetes is currently unknown. It has been suggested that it is related to several pathways, such as neuroendocrine disorders and the inflammatory response of the vascular endothelium [95]. Depression leads to overstimulation of the hypothalamic-pituitary-adrenal circuit, which causes an increase in cortisol secretion, which increases damage to the vascular endothelium and contributes to insulin resistance. It is also known that depression, diabetes, and cardiovascular disease may share several potential pleiotropic genes, thus affecting multiple signalling pathways, such as corticotropin-releasing hormone, adenosine monophosphate-activated protein kinase, and 5-hydroxytryptamine [96].

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Conclusions

The above materials emphasize the hypothesis that vascular depression can be a manifestation of more severe, profound, structural and functional changes in the body, associated with a more severe course and higher mortality from type 2 diabetes, coronary heart disease and other cardiovascular diseases.

Prospects for further research.

Further study of the mechanisms and connections between depressive disorders, diabetes and coronary heart disease would allow the development of pharmacological and non-pharmacological technologies to influence these processes and reduce aggravating chains, improve the prognosis of diseases, and improve the quality of life of patients.

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