Sensing ceramides by CYSLTR2 and P2RY6 to aggravate atherosclerosis.

Recent evidence shows elevated circulating long-chain ceramide levels predict atherosclerotic cardiovascular disease (ASCVD) independently of cholesterol. Although targeting ceramide signaling may provide therapeutic benefits beyond the treatment of hypercholesterolemia, the underlying mechanism by which circulating ceramides aggravate ASCVD remains elusive. We examined whether circulating long-chain ceramides activate membrane G protein-coupled receptors (GPCRs) to exacerbate atherosclerosis.

METTL3-catalyzed m6A methylation facilitates the contribution of vascular smooth muscle cells to atherosclerosis.

Aims: Vascular smooth muscle cells (VSMCs) are involved in the etiology of atherosclerosis, but whether methyltransferase-like 3 (METTL3)-catalyzed N6-methyladenosine (m6A) modulates the contribution of VSMCs to atherosclerosis remains elusive.

Methods And Results: We generated tamoxifen-inducible VSMC-specific METTL3 knockout mice with VSMC lineage tracing, and found that VSMC-specific METTL3 deficiency substantially attenuated atherosclerosis and reduced the proportion of VSMCs in plaques, due to the inhibition of VSMC atheroprone phenotype as characterized by macrophage-like and inflammatory features as well as high migratory and proliferative capacity. m6A-methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with polysome profiling analysis mechanistically displayed METTL3 catalyzed m6A methylation of myocardin-related transcription factor A (MRTFA) mRNA, and further enhanced YTH N6-methyladenosine RNA binding protein F3 (YTHDF3)-dependent MRTFA mRNA translation.

Ablation of the gut microbiota alleviates high-methionine diet-induced hyperhomocysteinemia and glucose intolerance in mice.

A high-methionine (HM) diet leads to hyperhomocysteinemia (HHcy), while gastrointestinal tissue is an important site of net homocysteine (Hcy) production. However, the role of the gut microbiota in host HHcy remains obscure. This study aimed to determine whether gut microbiota ablation could alleviate host HHcy and glucose intolerance and reveal the underlying mechanism.

ADAMTS7-Mediated Complement Factor H Degradation Potentiates Complement Activation to Contributing to Renal Injuries.

Background: The dysfunction of complement factor H (CFH), the main soluble complement negative regulator, potentiates various complement-induced renal injuries. However, insights into the underlying mechanism of CFH dysfunction remain limited. In this study, we investigated whether extracellular protease-mediated degradation accounts for CFH dysfunction in complement-mediated renal injuries.

Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia.

Background: The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents.

Methods: We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant.

Nidogen-2 is a Novel Endogenous Ligand of LGR4 to Inhibit Vascular Calcification.

Background: Vascular calcification is closely related to the all-cause mortality of cardiovascular events. Basement membrane protein nidogen-2 is a key component of the vascular extracellular matrix microenvironment and we recently found it is pivotal for the maintenance of contractile phenotype in vascular smooth muscle cells (VSMCs). However, whether nidogen-2 is involved in VSMCs osteochondrogenic transition and vascular calcification remains unclear.

PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing.

Background: Phenotypic transition of vascular smooth muscle cells (VSMCs) accounts for the pathogenesis of a variety of vascular diseases during the early stage. Recent studies indicate the metabolic reprogramming may be involved in VSMC phenotypic transition. However, the definite molecules that link energy metabolism to distinct VSMC phenotype remain elusive.

MFN2 Prevents Neointimal Hyperplasia in Vein Grafts via Destabilizing PFK1.

Background: Mechanical forces play crucial roles in neointimal hyperplasia after vein grafting; yet, our understanding of their influences on vascular smooth muscle cell (VSMC) activation remains rudimentary.

Methods: A cuff mouse model was used to study vein graft hyperplasia. Fifteen percent to 1 Hz uniaxial cyclic stretch (arterial strain), 5% to 1 Hz uniaxial cyclic stretch or a static condition (venous strain) were applied to the cultured VSMCs.

Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a lethal cardiovascular disease, and there is no proven drug treatment for this condition. In this study, by using the Connectivity Map (CMap) approach, we explored naringenin, a naturally occurring citrus flavonoid, as a putative agent for inhibiting AAA. We then validated the prediction with two independent mouse models of AAA, calcium phosphate (CaPO)-induced C57BL/6J mice and angiotensin II-infused ApoE mice.

Unspliced XBP1 Counteracts β-Catenin to Inhibit Vascular Calcification.

Background: Vascular calcification is a prevalent complication in chronic kidney disease and contributes to increased cardiovascular morbidity and mortality. XBP1 (X-box binding protein 1), existing as the XBP1u (unspliced XBP1) and XBP1s (spliced XBP1) forms, is a key component of the endoplasmic reticulum stress involved in vascular diseases. However, whether XBP1u participates in the development of vascular calcification remains unclear.

Nidogen-2 Maintains the Contractile Phenotype of Vascular Smooth Muscle Cells and Prevents Neointima Formation via Bridging Jagged1-Notch3 Signaling.

Background: How the extracellular matrix (ECM) microenvironment modulates the contractile phenotype of vascular smooth muscle cells (VSMCs) and confers vascular homeostasis remains elusive.

Methods: To explore the key ECM proteins in the maintenance of the contractile phenotype of VSMCs, we applied protein-protein interaction network analysis to explore novel ECM proteins associated with the VSMC phenotype. By combining in vitro and in vivo genetic mice vascular injury models, we identified nidogen-2, a basement membrane glycoprotein, as a key ECM protein for maintenance of vascular smooth muscle cell identity.

LOXL4 Abrogation Does Not Exaggerate Angiotensin II-Induced Thoracic or Abdominal Aortic Aneurysm in Mice.

It has been shown that thoracic aortic aneurysm and dissection (TAAD) could be a Mendelian trait caused by a single gene mutation. The gene mutation leads to the development of human TAAD. The gene is a member of the lysyl oxidase gene family.

Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury.

Compelling evidence has revealed that biased activation of G protein-coupled receptor (GPCR) signaling, including angiotensin II (AngII) receptor type 1 (AT1) signaling, plays pivotal roles in vascular homeostasis and injury, but whether a clinically relevant endogenous biased antagonism of AT1 signaling exists under physiological and pathophysiological conditions has not been clearly elucidated. Here, we show that an extracellular matrix protein, cartilage oligomeric matrix protein (COMP), acts as an endogenous allosteric biased modulator of the AT1 receptor and its deficiency is clinically associated with abdominal aortic aneurysm (AAA) development. COMP directly interacts with the extracellular N-terminus of the AT1 via its EGF domain and inhibits AT1-β-arrestin-2 signaling, but not Gq or Gi signaling, in a selective manner through allosteric regulation of AT1 intracellular conformational states.

Extracellular matrix dynamics in vascular remodeling.

Vascular remodeling is the adaptive response to various physiological and pathophysiological alterations that are closely related to aging and vascular diseases. Understanding the mechanistic regulation of vascular remodeling may be favorable for discovering potential therapeutic targets and strategies. The extracellular matrix (ECM), including matrix proteins and their degradative metalloproteases, serves as the main component of the microenvironment and exhibits dynamic changes during vascular remodeling.

COMP-prohibitin 2 interaction maintains mitochondrial homeostasis and controls smooth muscle cell identity.

Vascular smooth muscle cells (VSMCs) are highly phenotypically plastic, and loss of the contractile phenotype in VSMCs has been recognized at the early onset of the pathology of a variety of vascular diseases. However, the endogenous regulatory mechanism to maintain contractile phenotype in VSMCs remains elusive. Moreover, little has been known about the role of the mitochondrial bioenergetics in terms of VSMC homeostasis.

Cartilage oligomeric matrix protein prevents vascular aging and vascular smooth muscle cells senescence.

Aging-related vascular dysfunction contributes to cardiovascular morbidity and mortality. Cartilage oligomeric matrix protein (COMP), a vascular extracellular matrix protein, has been described as a negative regulatory factor for the vascular aging-related processes including atherosclerosis and vascular calcification. However, whether COMP is implicated in the process of vascular aging remains unclear.

Shift of Macrophage Phenotype Due to Cartilage Oligomeric Matrix Protein Deficiency Drives Atherosclerotic Calcification.

Rationale: Intimal calcification is highly correlated with atherosclerotic plaque burden, but the underlying mechanism is poorly understood. We recently reported that cartilage oligomeric matrix protein (COMP), a component of vascular extracellular matrix, is an endogenous inhibitor of vascular smooth muscle cell calcification.

Objective: To investigate whether COMP affects atherosclerotic calcification.