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Abstract: Hippo, an evolutionarily conserved kinase cascade reaction in organisms, can respond to a set of signals, such as mechanical signals and cell metabolism, to maintain cell growth, differentiation, tissue/organ development, and homeostasis. In the past ten years, Hippo has controlled the development of tissues and organs by regulating the process of cell proliferation, especially in the field of cardiac regeneration after myocardial infarction. This suggests that Hippo signaling is closely linked to cardiovascular disease. Atherosclerosis is the most common disease of the cardiovascular system. It is characterised by chronic inflammation of the vascular wall, mainly involving dysfunction of endothelial cells, smooth muscle cells, and macrophages. Oxidized Low density lipoprotein (LDL) damages the barrier function of endothelial cells, which enter the middle membrane of the vascular wall, accelerate the formation of foam cells, and promote the occurrence and development of atherosclerosis. Autophagy is associated with the development of atherosclerosis. However, the mechanism of Hippo regulation of atherosclerosis has not meant to be clarified. In view of the pivotal role of this signaling pathway in maintaining cell growth, proliferation, and differentiation, the imbalance of Hippo is related to atherosclerosis and related diseases. In this review, we emphasized Hippo as a hub for regulating atherosclerosis and discussed its potential targets in pathophysiology, human diseases, and related pharmacology.

Abstract: An abdominal aortic aneurysm (AAA) is a progressive dilatation of the vascular wall occurring below the aortic fissure, preferably occurring below the renal artery. The molecular mechanism of AAA has not yet been elucidated. In the past few decades, research on abdominal aortic aneurysm has been mainly focused on the vessel wall, and it is generally accepted that inflammation and middle layer fracture of the vessel wall is the core steps in the development of AAA. However, perivascular adipose tissue plays a non-negligible role in the occurrence and development of AAA. The position of PVAT plays a supporting and protective role on the vascular wall, but the particularity of the location makes it not only have the physiological function of visceral fat; but also can regulate the vascular function by secreting a large number of adipokines and cytokines. An abdominal aortic aneurysm is getting higher and higher, with a vascular rupture, low rescue success rate, and extremely high lethality rate. At present, there is no drug to control the progression or reverse abdominal aortic aneurysm. Therefore, it is critical to deeply explore the mechanism of abdominal aortic aneurysms and find new therapeutic ways to inhibit abdominal aortic aneurysm formation and disease progression. An abdominal aortic aneurysm is mainly characterized by inflammation of the vessel wall and matrix metalloprotein degradation. In this review, we mainly focus on the cytokines released by the perivascular adipose tissue, summarize the mechanisms involved in the regulation of abdominal aortic aneurysms, and provide new research directions for studying abdominal aortic aneurysms.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a secretory serine protease that plays multiple biological functions in the regulation of physiological and pathological processes. PCSK9 inhibitors decrease the circulating LDL-cholesterol level with well-known preventive and therapeutic effects on atherosclerosis (AS). Still, increasing evidence shows that the direct impact of PCSK9 on the vascular wall also plays an important role in atherosclerotic progression. Compared with other vascular cells, a large proportion of PCSK9 is originated from vascular smooth muscle cells (VSMC). Therefore, defining the effect of VSMC-derived PCSK9 on response changes, such as phenotypic switch, apoptosis, autophagy, inflammation, foam cell formation, and calcification of VSMC, helps us better understand the “pleiotropic” effects of VSMC on the atherosclerotic process. In addition, our understanding of the mechanisms of PCSK9 controlling VSMC functions in vivo is far from enough. This review aims to holistically evaluate and analyze the current state of our knowledge regarding PCSK9 actions affecting VSMC functions and its mechanism in atherosclerotic lesion development. A mechanistic understanding of PCSK9 effects on VSMC will further underpin the success of a new therapeutic strategy targeting AS.

Atherosclerosis is a chronic arterial wall illness that forms atherosclerotic plaques within the arteries. Plaque formation and endothelial dysfunction are atherosclerosis' characteristics. It is believed that the occurrence and development of atherosclerosis mainly include endothelial cell damage, lipoprotein deposition, inflammation and fibrous cap formation, but its molecular mechanism has not been elucidated. Therefore, protecting the vascular endothelium from damage is one of the key factors against atherosclerosis. The factors and processes involved in vascular endothelial injury are complex. Finding out the key factors and mechanisms of atherosclerosis caused by vascular endothelial injury is an important target for reversing and preventing atherosclerosis. Changes in cell adhesion are the early characteristics of EndMT, and cell adhesion is related to vascular endothelial injury and atherosclerosis. Recent researches have exhibited that endothelial-mesenchymal transition (EndMT) can urge atherosclerosis' progress, and it is expected that inhibition of EndMT will be an object for anti-atherosclerosis. We speculate whether inhibition of EndMT can become an effective target for reversing atherosclerosis by improving cell adhesion changes and vascular endothelial injury. Studies have shown that H2S has a strong cardiovascular protective effect. As H2S has anti- inflammatory, anti-oxidant, inhibiting foam cell formation, regulating ion channels and enhancing cell adhesion and endothelial functions, the current research on H2S in cardiovascular aspects is increasing, but anti-atherosclerosis's molecular mechanism and the function of H2S in EndMT have not been explicit. In order to explore the mechanism of H2S against atherosclerosis, to find an effective target to reverse atherosclerosis, we sum up the progress of EndMT promoting atherosclerosis, and Hydrogen sulfide's potential anti- EndMT effect is discussed in this review.

Coronary heart disease (CHD) is closely related to hypercholesterolemia, and lowering serum cholesterol is currently the most important strategy in reducing CHD. In humans, the serum cholesterol level is determined mainly by three metabolic pathways, namely, dietary cholesterol intake, cholesterol synthesis, and cholesterol degradation in vivo. An intervention that targets the key molecules in the three pathways is an important strategy in lowering serum lipids. Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) to reduce low-density lipoprotein (LDL) by about 20% to 45%. However, up to 15% of patients cannot tolerate the potential side effects of high statin dosages, and several patients also still do not reach their optimal LDL goals after being treated with statins. Ezetimibe inhibits cholesterol absorption by targeting the Niemann–Pick C1-like 1 protein (NPC1L1), which is related to cholesterol absorption in the intestines. Ezetimibe lowers LDL by about 18% when used alone and by an additional 25% when combined with statin therapy. The proprotein convertase subtilisin/kexin type 9 (PCSK9) increases hepatic LDLR degradation, thereby reducing the liver’s ability to remove LDL, which can lead to hypercholesterolemia. Evolocumab, which is a PCSK9 monoclonal antibody, can reduce LDL from baseline by 53% to 56%. The three drugs exert lipid-lowering effects by regulating the three key pathways in lipid metabolism. Combining any with the two other drugs on the basis of statin treatment has improved the lipid-lowering effect. Whether the combination of the three musketeers will reduce the side effects of monotherapy and achieve the lipid-lowering effect should be studied further in the future.

Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.