CNP Ameliorates Macrophage Inflammatory Response and Atherosclerosis.

BACKGROUND: CNP (C-type natriuretic peptide), an endogenous short peptide in the natriuretic peptide family, has emerged as an important regulator to govern vascular homeostasis. However, its role in the development of atherosclerosis remains unclear. This study aimed to investigate the impact of CNP on the progression of atherosclerotic plaques and elucidate its underlying mechanisms. METHODS: Plasma CNP levels were measured in patients with acute coronary syndrome. The potential atheroprotective role of CNP was evaluated in apolipoprotein E-deficient (ApoE-/-) mice through CNP supplementation via osmotic pumps, genetic overexpression, or LCZ696 administration. Various functional experiments involving CNP treatment were performed on primary macrophages derived from wild-type and CD36 (cluster of differentiation 36) knockout mice. Proteomics and multiple biochemical analyses were conducted to unravel the underlying mechanism. RESULTS: We observed a negative correlation between plasma CNP concentration and the burden of coronary atherosclerosis in patients. In early atherosclerotic plaques, CNP predominantly accumulated in macrophages but significantly decreased in advanced plaques. Supplementing CNP via osmotic pumps or genetic overexpression ameliorated atherosclerotic plaque formation and enhanced plaque stability in ApoE-/- mice. CNP promoted an anti-inflammatory macrophage phenotype and efferocytosis and reduced foam cell formation and necroptosis. Mechanistically, we found that CNP could accelerate HIF-1α (hypoxia-inducible factor 1-alpha) degradation in macrophages by enhancing the interaction between PHD (prolyl hydroxylase domain-containing protein) 2 and HIF-1α. Furthermore, we observed that CD36 bound to CNP and mediated its endocytosis in macrophages. Moreover, we demonstrated that the administration of LCZ696, an orally bioavailable drug recently approved for treating chronic heart failure with reduced ejection fraction, could amplify the bioactivity of CNP and ameliorate atherosclerotic plaque formation. CONCLUSIONS: Our study reveals that CNP enhanced plaque stability and alleviated macrophage inflammatory responses by promoting HIF-1α degradation, suggesting a novel atheroprotective role of CNP. Enhancing CNP bioactivity may offer a novel pharmacological strategy for treating related diseases.

Prostaglandin I2 signaling prevents angiotensin II-induced atrial remodeling and vulnerability to atrial fibrillation in mice.

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I2 (PGI2) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I2 receptor (IP). However, the role of PGI2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI2/IP system protects against atrial fibrosis and that PGI2 is a therapeutic target for treating AF.The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12.

Angiotensin receptor-neprilysin inhibitor attenuates cardiac hypertrophy and improves diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction.

LCZ696, an angiotensin receptor-neprilysin inhibitor, has shown promising clinical efficacy in patients with heart failure (HF) with reduced ejection fraction. However, its potential effects on heart failure with preserved ejection fraction (HFpEF) are still not fully understood. We evaluated the effect of LCZ696 on HFpEF in transverse aortic constriction mice and compared it with the effect of the angiotensin receptor blocker, valsartan. We found that LCZ696 improved cardiac diastolic function by reducing ventricular hypertrophy and fibrosis in mice with overload-induced diastolic dysfunction. In addition, there was superior inhibition of LCZ696 than stand-alone valsartan. As a potential underlying mechanism, we demonstrated that LCZ696 behaves as a potent suppressor of calcium-mediated calcineurin-nuclear factor of activated T cells (NFAT) signalling transduction pathways. Hence, we demonstrated the protective effects of LCZ696 in overload-induced HFpEF and provided a pharmaceutical therapeutic strategy for related diseases.

Serum Beta-2 Microglobulin: A Possible Biomarker for Atrial Fibrillation.

BACKGROUND Atrial fibrillation (AF) is the most common persistent arrhythmia that can cause complications (including stroke). Therefore, its diagnosis and treatment require increased attention. Although beta-2 microglobulin (b2-MG) is a novel marker of cardiovascular disease, its role in AF has not been evaluated. MATERIAL AND METHODS We conducted a case-control study with 61 patients who had normal heart rhythm (control group) and 60 patients with AF (research group). We analyzed the serum b2-MG levels in both groups and performed multivariate analysis to assess the correlation between b2-MG and left atrial remodeling. In addition, b2-MG levels were compared between the left atrial blood and peripheral venous blood of another set of 57 patients with AF, who underwent cryoballoon ablation. RESULTS There were no statistically significant differences in the baseline characteristics (age, sex, history of hypertension, diabetes mellitus, previous stroke, coronary heart disease, and estimated glomerular filtration rate) of the control and research groups. The left atrial anteroposterior diameters (LAD) and left ventricular end-systolic diameters in the AF group were significantly larger compared to the control group (P<0.01). Serum ß2-MG levels in patients with AF were significantly higher (P<0.01) and positively correlated with the LAD (B-coefficient 25.482, 95% CI 14.410~36.554, P<0.01), serum ß2-MG levels in the left atrial blood were significantly higher than those in peripheral venous blood (P<0.01), and serum ß2-MG levels were an independent predictor of AF. CONCLUSIONS With the development of atrial fibrillation, the serum ß2-MG levels increase and are closely related to the left atrial remodeling due to AF. Therefore, ß2-MG can be an effective biomarker for predicting AF.

[Research progress of eicosanoid metabolomics in cardiovascular diseases].

Eicosanoids are oxidized derivatives of 20-carbon polyunsaturated fatty acids (PUFAs). In recent years, the role and mechanism of eicosanoids in cardiovascular diseases have attracted extensive attention. Substrate PUFAs including arachidonic acid are metabolized by cyclooxygenase, lipoxygenase, cytochrome P450 oxidase enzymes, or non-enzymatic auto-oxidation. Eicosanoid metabolomics is an effective approach to study the complex metabolic network of eicosanoids. In this review, we discussed the biosynthesis and functional activities of eicosanoids, the strategies of eicosanoid metabolomics, and applications and research progress of eicosanoid metabolomics in cardiovascular diseases, which might offer new insights and strategies for the treatment of cardiovascular diseases.

Yes-Associated Protein Promotes Angiogenesis via Signal Transducer and Activator of Transcription 3 in Endothelial Cells.

RATIONALE: Angiogenesis is a complex process regulating endothelial cell (EC) functions. Emerging lines of evidence support that YAP (Yes-associated protein) plays an important role in regulating the angiogenic activity of ECs. OBJECTIVE: The objective of this study was to specify the effect of EC YAP on angiogenesis and its underlying mechanisms. METHOD AND RESULTS: In ECs, vascular endothelial growth factor reduced YAP phosphorylation time and dose dependently and increased its nuclear accumulation. Using Tie2Cre-mediated YAP transgenic mice, we found that YAP promoted angiogenesis in the postnatal retina and tumor tissues. Mass spectrometry revealed signal transducer and activator of transcription 3 (STAT3) as a potential binding partner of YAP in ECs. Western blot and immunoprecipitation assays indicated that binding with YAP prolonged interleukin 6-induced STAT3 nuclear accumulation by blocking chromosomal maintenance 1-mediated STAT3 nuclear export without affecting its phosphorylation. Moreover, angiopoietin-2 expression induced by STAT3 was enhanced by YAP overexpression in ECs. Finally, a selective STAT3 inhibitor or angiopoietin-2 blockage partly attenuated retinal angiogenesis in Tie2Cre-mediated YAP transgenic mice. CONCLUSIONS: YAP binding sustained STAT3 in the nucleus to enhance the latter's transcriptional activity and promote angiogenesis via regulation of angiopoietin-2.

Spectrum evaluation-assisted eicosanoid metabolomics for global eicosanoid profiling in human vascular endothelial cells.

Eicosanoids are hundreds of metabolites derived from poly-unsaturated fatty acids (PUFAs), which regulate biological processes from multiple angles via a complex metabolic network. Targeted eicosanoid metabolomics is used to study the eicosanoid profile in biological samples but only for eicosanoids with available standards. To expand the coverage of eicosanoids detected, we identified the eicosanoids without available standards by estimation of the retention time and comparison of the MS/MS spectra with the reference ones which was collected in a database from literature. Scheduled multiple reaction monitoring- information dependent acquisition- enhanced product ion (sMRM-IDA-EPI) scan mode was applied in this method, which was called Spectrum Evaluation-assisted Eicosanoid Metabolomics (SEEM). By using this method, 243 eicosanoids (167 without standards) could be relatively quantified with precision over 90 percent. We applied the method to analyze the global profile of eicosanoids secreted by human umbilical vascular endothelial cells at the basal level and with n-3 PUFA treatment. 26 putative eicosanoids showed altered levels, despite no available standards. In general, n-3 PUFA treatment increased most of their own metabolites and decreased the epoxy-, hydroxyl- and keto- linoleic acid metabolites. The application of the SEEM method proved its potency of identification and quantification of eicosanoids without standards.

Endothelial ATP-binding cassette G1 in mouse endothelium protects against hemodynamic-induced atherosclerosis.

Activated vascular endothelium inflammation under persistent hyperlipidemia is the initial step of atherogenesis. ATP-binding cassette G1 (ABCG1) is a crucial factor maintaining sterol and lipid homeostasis by transporting cholesterol efflux to high-density lipoprotein. In this study, we investigated the protective effects of ABCG1 in endothelial inflammation activation during early-stage atherogenesis in mice and the underlying mechanisms. Endothelial cell (EC)-specific ABCG1 transgenic (EC-ABCG1-Tg) mice were generated and cross-bred with low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. After a 4-week Western-type diet, the mice were sacrificed for assessing atherosclerosis. Human umbilical vein ECs were treated with different flows, and ABCG1 was adenovirally overexpressed to investigate the mechanism in vitro. Compared with Ldlr(-/-) mouse aortas, EC-ABCG1-Tg/Ldlr(-/-) aortas showed decreased early-stage lesions. Furthermore, the lesion area in the EC-ABCG1-Tg/Ldlr(-/-) mouse aortic arch but not thoracic aorta was significantly reduced, which suggests a protective role of ABCG1 under atheroprone flow. In vitro, overexpression of ABCG1 attenuated EC activation caused by oscillatory shear stress. Overexpression of ABCG1 blunted cholesterol-activated ECs in vitro. In exploring the mechanisms of ABCG1 attenuating endothelial inflammation, we found that ABCG1 inhibited oscillatory flow-activated nuclear factor kappa B and NLRP3 inflammasome in ECs. ABCG1 may play a protective role in early-stage atherosclerosis by reducing endothelial activation induced by oscillatory shear stress via suppressing the inflammatory response.

20-Hydroxyeicosatetraenoic acid involved in endothelial activation and thrombosis.

Endothelial cells play an important role in the process of coagulation and the function of platelets. We have previously reported that 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite of arachidonic acid, increased platelet aggregation and induced hemostasis. The purpose of the present study is to investigate whether 20-HETE-mediated endothelial activation has effect on the coagulation and platelet aggregation. C57Bl/6 mice were treated with PBS or 20-HETE (20 µg/kg) for 2 h, and then we performed a carotid artery or femoral artery thrombosis model by FeCl3. Detection of blood flow indicated that 20-HETE pretreatment accelerated formation of thrombus in both common carotid artery and femoral artery. In vitro, the secretion and expression of von Willebrand factor (vWF) in cultured human umbilical vein endothelial cells (HUVECs) with 20-HETE stimulation were increased, subsequently. The protein level of vWF in HUVECs was decreased at 1 h but increased with prolonged treatment with 20-HETE (>4 h). In contrast, vWF in the culture medium was increased under administration of 20-HETE at 1 h. As a result, adhesion of platelets on HUVECs was significantly increased by 20-HETE. In HUVECs, the extracellular signal-regulated kinase (ERK) pathway was activated by 20-HETE in a dose-dependent manner, and the inhibitors of ERK and L-type Ca(2+) channel blocked the release of vWF mediated by 20-HETE. In conclusion, 20-HETE instigates endothelial activation and induces the expression and secretion of vWF via the activation of ERK and calcium channel and therefore triggers thrombosis.

IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling.

RATIONALE: Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are important mechanisms of atrial remodeling, predisposing to the development of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). However, the molecular mechanisms underlying these processes especially their interactions have not been fully elucidated. OBJECTIVE: To explore the potential role of ER stress-mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes. METHODS AND RESULTS: Mouse atrial cardiomyocytes (HL-1 cells) and rats with T2DM were used as study models. Significant ER stress was observed in the diabetic rat atria. After treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) identified several known ER stress and calmodulin proteins, including heat shock protein family A (HSP70) member [HSPA] 5 [GRP78]) and HSPA9 (GRP75, glucose-regulated protein 75). In situ proximity ligation assay indicated that TM led to increased protein expression of the IP3R1-GRP75-VDAC1 (inositol 1,4,5-trisphosphate receptor 1-glucose-regulated protein 75-voltage-dependent anion channel 1) complex in HL-1 cells. Small interfering RNA silencing of GRP75 in HL-1 cells and GRP75 conditional knockout in a mouse model led to impaired calcium transport from the ER to the mitochondria and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuated atrial remodeling and AF progression in Myh6-Cre+/Hspa9flox/flox + TM mice. CONCLUSIONS: The IP3R1-GRP75-VDAC1 complex mediates ER stress-mitochondrial oxidative stress and plays an important role in diabetic atrial remodeling.

Lipidomics Revealed Alteration of Sphingolipid Metabolism During the Reparative Phase After Myocardial Infarction Injury.

Aberrant sphingolipid metabolism contributes to cardiac pathophysiology. Emerging evidence found that an increased level of ceramide during the inflammatory phase of post-myocardial infarction (MI) served as a biomarker and was associated with cardiac dysfunction. However, the alternation of the sphingolipid profile during the reparative phase after MI is still not fully understood. Using a mouse model of the left anterior descending ligation that leads to MI, we performed metabolomics studies to assess the alternations of both plasma and myocardial sphingolipid profiles during the reparative phase post-MI. A total number of 193 sphingolipid metabolites were detected. Myocardial sphingolipids but not plasma sphingolipids showed marked change after MI injury. Ceramide-1-phosphates, which were accumulated after MI, contributed highly to the difference in sphingolipid profiles between groups. Consistently, the expression of ceramide kinase, which phosphorylates ceramides to generate ceramide-1-phosphates, was upregulated in heart tissue after MI injury. Our findings revealed the altering sphingolipid metabolism during the reparative phase post-MI and highlighted the potential role of ceramide kinase/ceramide-1-phosphate in ischemic heart disease.

Ivabradine Ameliorates Cardiac Function in Heart Failure with Preserved and Reduced Ejection Fraction via Upregulation of miR-133a.

Heart failure (HF) is a clinical syndrome caused by impairment of ventricular filling, ejection of blood, or both and is categorized as HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF) based on left ventricular function. Cardiac fibrosis contributes to left ventricular dysfunction and leads to the development of HF. Ivabradine, an If current selective specific inhibitor, has been shown to improve the prognosis of patients with HF. However, the effects of ivabradine on cardiac function and fibrosis in HFpEF and HFrEF and the underlying mechanism remain unclear. In the present study, we utilized mouse models to mimic HFpEF and HFrEF and evaluated the therapeutic effects of ivabradine. By treating mice with different doses (10 mg/kg/d and 20 mg/kg/d) of ivabradine for 4 or 8 weeks, we found that a high dose of ivabradine improved cardiac diastolic function in HFpEF mice and ameliorated cardiac diastolic and systolic function and ventricular tachycardia incidence in HFrEF mice. Moreover, ivabradine significantly reduced the activation of cardiac fibroblasts and myocardial fibrosis in mice. Mechanistically, microRNA-133a, which was upregulated by ivabradine, targeted connective tissue growth factor and collagen 1 in cardiac fibroblasts and might contribute to the protective role of ivabradine. Together, our work utilized mouse models to study HFpEF and HFrEF, demonstrated the protective role of ivabradine in HFpEF and HFrEF, and elucidated the potential underlying mechanism, which provides an effective strategy for related diseases.

Renal protective effects and mechanisms of the angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome.

AIMS: This study investigated the renal protective effects and mechanisms of angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome. MATERIALS AND METHODS: Mice were divided into abdominal aortic ligation alone, or treatment with LCZ696 or valsartan, whilst those undergoing sham surgery served as controls. Rat proximal renal tubular epithelial cells from the NRK-52E line were treated with control solution, LCZ696 or valsartan, in the presence or absence of Ang II for 24 h. KEY FINDINGS: Compared to controls, abdominal aortic ligation significantly increased plasma NT-proBNP and urine neutrophil gelatinase-associated lipocalin (NGAL), which were associated with reduced renal length and velocity time integral on ultrasonography. Histology revealed wrinkling of the glomerular capillary wall and sclerosis of the glomerulus, dilatation of the Bowman's capsule, accompanied by diffuse renal tubular atrophy and fibrosis, accompanied by lower kidney index and higher percentage area of fibrosis. Increases in NGAL and decreased ANP protein and mRNA expression levels were observed. These abnormalities were significantly prevented by LCZ696 and to a lesser extent by valsartan. Cellular experiments demonstrated a central role of Ang II/transforming growth factor-ß1/Smad2/3/connective tissue growth factor-dependent signaling leading to type IV collagen deposition. This upregulation was reversed by LCZ696 in a greater extent than valsartan treatment alone, accompanied by a significant improvement in NGAL. SIGNIFICANCE: LCZ696 can reduce kidney injury to a level beyond valsartan therapy alone in mice with cardiorenal syndrome, which can be speculated by effects on epithelial-mesenchymal transition and fibrosis through downregulating the TGF-ß1/Smad2/3/CTGF/Collagen IV pathway.

Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis.

Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), known to be independently associated with cardiovascular diseases. However, the effect of IH on cardiac fibrosis and molecular events involved in this process are unclear. Here, we tested IH in angiotensin II (Ang II)-induced cardiac fibrosis and signaling linked to fibroblast activation. IH triggered cardiac fibrosis and aggravated Ang II-induced cardiac dysfunction in mice. Plasma thrombospondin-1 (TSP1) content was upregulated in both IH-exposed mice and OSA patients. Moreover, both in vivo and in vitro results showed IH-induced cardiac fibroblast activation and increased TSP1 expression in cardiac fibroblasts. Mechanistically, phosphorylation of STAT3 at Tyr705 mediated the IH-induced TSP1 expression and fibroblast activation. Finally, STAT3 inhibitor S3I-201 or AAV9 carrying a periostin promoter driving the expression of shRNA targeting Stat3 significantly attenuated the synergistic effects of IH and Ang II on cardiac fibrosis in mice. This work suggests a potential therapeutic strategy for OSA-related fibrotic heart disease.

Hyperglycemia Induces Endoplasmic Reticulum Stress in Atrial Cardiomyocytes, and Mitofusin-2 Downregulation Prevents Mitochondrial Dysfunction and Subsequent Cell Death.

Mitochondrial oxidative stress and dysfunction play an important role of atrial remodeling and atrial fibrillation (AF) in diabetes mellitus. Endoplasmic reticulum (ER) stress has been linked to both physiological and pathological states including diabetes. The aim of this project is to explore the roles of ER stress in hyperglycemia-induced mitochondrial dysfunction and cell death of atrial cardiomyocytes. High glucose upregulated ER stress, mitochondrial oxidative stress, and mitochondria-associated ER membrane (MAM)- enriched proteins (such as glucose-regulated protein 75 (GRP75) and mitofusin-2 (Mfn2)) of primary cardiomyocytes in vitro. Sodium phenylbutyrate (4-PBA) prevented the above changes. Silencing of Mfn2 in HL-1 cells decreased the Ca2+ transfer from ER to mitochondria under ER stress conditions, which were induced by the ER stress agonist, tunicamycin (TM). Electron microscopy data suggested that Mfn2 siRNA significantly disrupted ER-mitochondria tethering in ER stress-injured HL-1 cells. Mfn2 silencing attenuated mitochondrial oxidative stress and Ca2+ overload, increased mitochondrial membrane potential and mitochondrial oxygen consumption, and protected cells from TM-induced apoptosis. In summary, Mfn2 plays an important role in high glucose-induced ER stress in atrial cardiomyocytes, and Mfn2 silencing prevents mitochondrial Ca2+ overload-mediated mitochondrial dysfunction, thereby decreasing ER stress-mediated cardiomyocyte cell death.

Sacubitril/Valsartan Improves Left Atrial and Left Atrial Appendage Function in Patients With Atrial Fibrillation and in Pressure Overload-Induced Mice.

LCZ696 (sacubitril/valsartan) is an angiotensin receptor-neprilysin inhibitor and has shown beneficial effects in patients with heart failure. However, whether LCZ696 protects against left atrial (LA) and LA appendage (LAA) dysfunction is still unclear. The present study aimed to assess the efficacy of LCZ696 for improving the function of LA and LAA. We performed both a retrospective study comparing LCZ696 with angiotensin receptor blockers (ARBs) to assess the efficacy of LCZ696 in patients with atrial fibrillation and an animal study in a mouse model with pressure overload. LA peak systolic strain, LAA emptying flow velocity, and LAA ejection fraction (LAAEF) were significantly increased in patients with LCZ696 as compared with ARBs (p = 0.024, p = 0.036, p = 0.026, respectively). Users of LCZ696 had a lower incidence of spontaneous echocardiography contrast (p = 0.040). Next, patients were divided into two groups (LAAEF ≤ 20% and > 20%). Administration of LCZ696 in patients with LAAEF > 20% was more frequent than LAAEF ≤ 20% (p = 0.032). Even after controlling for LAA dysfunction-related risk factors (age, atrial fibrillation type, old myocardial infarction, hypertension, congestive heart failure, and prior stroke or transient ischemic attack), use of LCZ696 remained significantly associated with reduced probability of LAAEF ≤ 20% [odds ratio = 0.011; 95% confidence interval (0.000-0.533), p = 0.023]. To further confirmed effect of LCZ696 in LA function, we constructed a post-transverse aortic constriction model in mice. Mice with LCZ696 treatment showed lower LA dimension and higher left ventricular ejection fraction and LAA emptying flow velocity as compared with mice with vehicle or valsartan treatment. Meanwhile, as compared with vehicle or valsartan, LCZ696 significantly decreased LA fibrosis in mice. In summary, we provide evidence that LCZ696 may be more effective in improving LA and LAA function than ARBs in both humans and mice, which suggests that LCZ696 might be evaluated as a direct therapeutic for atrial remodeling and AF.

The role of Hippo/yes-associated protein signalling in vascular remodelling associated with cardiovascular disease.

Vascular remodelling is a vital process of a wide range of cardiovascular diseases and represents the altered structure and arrangement of blood vessels. The Hippo pathway controls organ size by regulating cell survival, proliferation and apoptosis. Yes-associated protein (YAP), a transcription coactivator, is a downstream effector of the Hippo pathway. There is growing evidence for the importance of the Hippo/YAP pathway in vascular-remodelling and related cardiovascular diseases. The Hippo/YAP pathway alters extracellular matrix production or degradation and the growth, death and migration of vascular smooth muscle cells and endothelial cells, which contributes to vascular remodelling in cardiovascular diseases such as pulmonary hypertension, atherosclerosis, restenosis, aortic aneurysms and angiogenesis. In this review, we summarize and discuss recent findings about the roles and mechanisms of Hippo/YAP signalling in vascular remodelling and related conditions. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.