Introduction

Diabetes mellitus, characterized by abnormally elevated blood glucose levels, is one of the twenty-first century's fastest growing challenges. According to the International Diabetes Federation (IDF), 1 in 10 adults (age 20–79 years; 537 million individuals) had diabetes in 2021, with the number expected to reach 783 million by 2045 [1]. Patients suffer mostly from chronic complications, including macrovascular and microvascular disease. Macrovascular complications result from lesions to the arteries, leading to large vessel obstructions such as coronary artery disease, atherosclerosis, and peripheral vascular disease [2]. Microvascular complications, characterized by microvascular injuries, include retinopathy, nephropathy, and neuropathy. Atherosclerotic cardiovascular disease (ASCVD), which manifests as coronary heart disease, ischemic stroke, peripheral artery disease, and heart failure, remains the leading cause of death and disability among patients with diabetes mellitus [3]. Hyperglycemia is regarded as the most important factor in the mechanism of diabetic complications, and it has been shown to activate several pathways, including the polyol, nonenzymatic glycation, and advanced glycation end product (AGE) pathways, the production of reactive oxygen species (ROS), and the diacylglycerol (DAG)-protein kinase C (PKC) pathway [2].

The PKCs are a family of serine/threonine-related protein kinases that play indispensable roles in several signal transduction pathways and cellular functions [2]. PKCδ is a PKC isoform belonging to the novel PKC (nPKC) subgroup that is Ca2+-independent and phospholipid- and DAG-activated [4]. PKCδ was found to be activated in a number of atherosclerotic cardiovascular diseases as well as diabetic complications, indicating that it may be a mediator of diabetes-related atherosclerosis. Atherosclerosis is a complex process involving various types of cells, including endothelial cells (ECs), vascular smooth muscle cells (VSMCs), monocytes/macrophages, and so on. To determine the expression of PKCδ in ECs, VSMCs, and macrophages in human vessels, we stained paraffin sections of a vessel from the amputated limb of a male diabetes patient, with his informed consent (Fig. 1). He experienced pain at rest due to severe arterial atherosclerotic occlusions in the left lower extremity and amputation was indicated. The patient was well informed, and several vessels were collected after amputation. The staining was from a non-occluded artery with thin neointima. Markers of ECs (CD31), VSMCs (α-SMA), and macrophages (CD68) were stained green and the marker of PKCδ was stained red. Although the functions of PKCδ have been discussed in previous reviews, they have not been reviewed in detail [5, 6]. In this review, we summarize the role of PKCδ in regulating the dysfunction of endothelial cells, vascular smooth muscle cells, and monocytes/macrophages in non-DM and DM conditions to provide a comprehensive understanding of the role of PKCδ in diabetic atherosclerosis.

Fig. 1
figure 1

PKCδ, CD31, α-SMA, and CD68 staining in a femoral artery tissue from lower limb of a 60 years diabetes patient who had underwent an amputation surgery (A, B). Representative images of HE staining of vessels. C Positive co-staining of CD31/PKCδ was observed in intimal layer. CD31 shown in green, PKCδ in red, and DAPI in blue. D Positive co-staining of α-SMA/PKCδ was observed in media layer. α-SMA shown in green, PKCδ in red, and DAPI in blue. E Positive co-staining of CD68/PKCδ was observed in neointimal and adventitial layers. CD68 shown in green, PKCδ in red, and DAPI in blue. The magnification scale of HE image was 5X. Arrows show positive colocalized staining. L, lumen; M, media; N, neointima; Adv, adventitia

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PKCδ in the dysfunction of endothelial cells

Endothelial cells dysfunction leads to the earliest detectable changes, such as focal permeation, trap**, and physicochemical modification of circulating lipoprotein particles in the sub-endothelial space, and plays a vital role in the pathophysiology of atherosclerosis. Endothelial dysfunction is characterized by impaired endothelium-dependent vasodilation, hyperpermeability, leukocytes adhesion, chronic inflammation, heightened oxidative stress, endothelial-to-mesenchymal transition, and endothelial cells senescence and apoptosis [7].

Healthy endothelium regulates vascular tone and structure and protects vessels from thrombosis [8]. Impaired vascular tone can lead to increased endothelial permeability, platelet aggregation, leukocytes adhesion, and the generation of cytokines. Hyperpermeability can be induced by a variety of cytokines, including vascular endothelial growth factor (VEGF), histamine, and thrombin, as well as other factors, such as high levels of oxidative stress and inflammation [7]. Damage to endothelial barrier integrity leads to lower NO availability, vascular swelling/edema, and abnormal hemostasis. Under pathologic conditions, the expression of adhesion molecules such as VCAM-1, ICAM-1, E-selectin, and MCP-1 is induced by proinflammatory mediators. These adhesion molecules enhance leukocytes adhesion and transmigration while also triggering inflammation, which is at the core of atherosclerosis. Furthermore, heightened oxidative stress facilitates the formation of ox-LDL, activates endothelial cells, upregulates adhesion molecule expression, alters vascular tone, and leads to EC apoptosis [9,

Perspectives

In this review, we discussed the role of PKCδ in regulating several pathophysiologic changes of VSMCs, ECs, and monocytes/macrophages in the process of atherosclerotic plaque formation under DM and non-DM conditions. However, both upregulation and downregulation of PKCδ can lead to similar effects (Supplementary table 1). We reviewed literatures focusing on the function of PKCδ in PKCδ-overexpressed mice but found little evidence. Mice with liver-specific overexpression of PKCδ showed decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis [114]. Epidermis-specific overexpression of PKCδ inhibited skin tumor formation [146]. Thus, more high-quality evidence from PKCδ downregulated or overexpressed DM animals is required. In addition, atherosclerosis is a complex inflammatory disease that involves not just those three types of cells, but also lymphocytes, NK cells, dendritic cells, neutrophils, and others. The importance of these cells in the formation of atherosclerotic lesions and of PKCδ needs to be further explored. Calcium dobesilate is a clinically available drug mainly used in the treatment of diabetic retinopathy and deep venous insufficiency. It was also shown to inhibit monocytes differentiation via PKCδ inhibition, indicating a possible role of calcium dobesilate in the treatment of atherosclerosis. Rottlerin and siRNA, the two most commonly used PKCδ inhibitors, have been proven to alleviate the VSMCs, ECs, and monocytes/macrophages dysfunction. Other natural extracts, such as polydatin and curcumin, have also been proven to protect endothelial cells via PKCδ suppression. Their application in clinical practice is also worth investigating.