Ambulatory blood pressure monitoring profiles in Asia.

High blood pressure (BP) remains a major health problem globally, with a proportion of hypertension-mediated organ damage (HMOD) increasing worldwide including in Asia region. Cardiovascular (CV), cerebral and kidney diseases related to hypertension were reported to be closely associated with morning surge and nocturnal hypertension-a subset of BP variability-which can be detected by out-of-office BP measurement. Ambulatory BP monitoring (ABPM) and Home BP monitoring (HBPM) have been recommended by major guidelines to be used in the evaluation of BP variability and outcomes' prediction of hypertension patients. However, an interesting profile of ABPM in Asia has been reported and hypothesized to correlate with different outcomes. This review will focus on the current recommendation of ABPM use by the guidelines, the major different profiles of ABPM in Asia as compared to Western countries according to clinical indications, and the challenges in implementing optimal use of ABPM in Asian countries based on available evidence.

How Well Do AI-Enabled Decision Support Systems Perform in Clinical Settings?

Real-world performance of machine learning (ML) models is crucial for safely and effectively embedding them into clinical decision support (CDS) systems. We examined evidence about the performance of contemporary ML-based CDS in clinical settings. A systematic search of four bibliographic databases identified 32 studies over a 5-year period. The CDS task, ML type, ML method and real-world performance was extracted and analysed. Most ML-based CDS supported image recognition and interpretation (n=12; 38%) and risk assessment (n=9; 28%). The majority used supervised learning (n=28; 88%) to train random forests (n=7; 22%) and convolutional neural networks (n=7; 22%). Only 12 studies reported real-world performance using heterogenous metrics; and performance degraded in clinical settings compared to model validation. The reporting of model performance is fundamental to ensuring safe and effective use of ML-based CDS in clinical settings. There remain opportunities to improve reporting.

Gender Differences of Gly972Arg Polymorphism of the IRS-1 Gene Related to Cardiovascular Disease Risk Factors Among Indonesians.

BACKGROUND: Cardiovascular disease is driven by traditional risk factors, sex, and genetic differences. The Asian population, specifically Indonesians, has been known at high risk of insulin resistance and endothelial dysfunction. A possible genetic risk factor related to cardiovascular diseases is Gly972Arg polymorphism of insulin receptor substrate 1 (IRS-1) gene, as this impairs endothelial function. To date, whether there is a gender difference in Gly972Arg polymorphism of the IRS-1 gene in Indonesians is unknown. This study aimed to to define whether there is a gender difference in Gly972Arg polymorphism of the IRS-1 gene in Indonesians. METHODS: We studied adults living in two areas (rural and urban) in Indonesia. We collected demographic and clinical data from the study subjects. Gly972Arg polymorphism of the IRS-1 gene (rs1801278) was detected using TaqMan real-time polymerase chain reaction. RESULTS: A total of 378 subjects were recruited. The wild-type allele (CC) was found in 86 (22.8%) subjects, heterozygous mutant allele (CT) in 245 (64.8%), and homozygous mutant allele in 47 (12.4%). The proportion of subjects with T alleles was significantly higher among women than men (54.6% vs. 45.4%, odds ratio: 1.89; p = 0.01). Subjects with T allele more often have hypertension (odds ratio: 1.69, p = 0.058). CONCLUSION: There were a higher proportion of women than men carrying the T allele of Gly972Arg polymorphism among Indonesians. Individuals with the T allele appeared to show a greater prevalence of hypertension. These results may explain a possible mechanism of the high prevalence of metabolic syndrome in Indonesia, especially in women.

Validation of EuroSCORE II Scoring System on Isolated CABG Patient in Indonesia.

BACKGROUND: Coronary Artery Bypass Graft (CABG) is one solution to overcome cardiovascular problems. EuroSCORE II is a scoring system to predict mortality risk in patients undergoing cardiac surgery including CABG. Unfortunately, there's still much debate about the benefits of EuroSCORE II in Asia, including Indonesia. This study aims to validates EuroSCORE II in predicting the outcomes in patients underwent CABG without any other procedure. RESULTS: A total of 2628 patients were included. The mean age was 59 years, mostly male (84.97%; n = 2233). Most patients underwent elective surgery (93.07%; n = 2446) and only 1.67% (n = 44) of the patients has high EuroSCORE category. Death was found in 4.22% (n-111) patients. EuroSCORE II had fair discriminant power (AUC 0.72), but a lower mortality predicted value for each group. CONCLUSION: The parameters in EuroSCORE II are related with mortality in isolated CABG patients, but they cannot be used as mortality predictors in Indonesia.

Effects of machine learning-based clinical decision support systems on decision-making, care delivery, and patient outcomes: a scoping review.

OBJECTIVE: This study aims to summarize the research literature evaluating machine learning (ML)-based clinical decision support (CDS) systems in healthcare settings. MATERIALS AND METHODS: We conducted a review in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Review). Four databases, including PubMed, Medline, Embase, and Scopus were searched for studies published from January 2016 to April 2021 evaluating the use of ML-based CDS in clinical settings. We extracted the study design, care setting, clinical task, CDS task, and ML method. The level of CDS autonomy was examined using a previously published 3-level classification based on the division of clinical tasks between the clinician and CDS; effects on decision-making, care delivery, and patient outcomes were summarized. RESULTS: Thirty-two studies evaluating the use of ML-based CDS in clinical settings were identified. All were undertaken in developed countries and largely in secondary and tertiary care settings. The most common clinical tasks supported by ML-based CDS were image recognition and interpretation (n = 12) and risk assessment (n = 9). The majority of studies examined assistive CDS (n = 23) which required clinicians to confirm or approve CDS recommendations for risk assessment in sepsis and for interpreting cancerous lesions in colonoscopy. Effects on decision-making, care delivery, and patient outcomes were mixed. CONCLUSION: ML-based CDS are being evaluated in many clinical areas. There remain many opportunities to apply and evaluate effects of ML-based CDS on decision-making, care delivery, and patient outcomes, particularly in resource-constrained settings.

Platelet Glycoprotein-Ib (GPIb) May Serve as a Bridge between Type 2 Diabetes Mellitus (T2DM) and Atherosclerosis, Making It a Potential Target for Antiplatelet Agents in T2DM Patients.

Type 2 diabetes mellitus (T2DM) is a persistent metabolic condition that contributes to the development of cardiovascular diseases. Numerous studies have provided evidence that individuals with T2DM are at a greater risk of developing cardiovascular diseases, typically two to four times more likely than those without T2DM, mainly due to an increased risk of atherosclerosis. The rupture of an atherosclerotic plaque leading to pathological thrombosis is commonly recognized as a significant factor in advancing cardiovascular diseases caused by TD2M, with platelets inducing the impact of plaque rupture in established atherosclerosis and predisposing to the primary expansion of atherosclerosis. Studies suggest that individuals with T2DM have platelets that display higher baseline activation and reactivity than those without the condition. The expression enhancement of several platelet receptors is known to regulate platelet activation signaling, including platelet glycoprotein-Ib (GPIb). Furthermore, the high expression of platelet GP1b has been reported to increase the risk of platelet adhesion, platelet-leucocyte interaction, and thrombo-inflammatory pathology. However, the study exploring the role of GP1b in promoting platelet activation-induced cardiovascular diseases in T2DM patients is still limited. Therefore, we summarize the important findings regarding pathophysiological continuity between T2DM, platelet GPIb, and atherosclerosis and highlight the potential therapy targeting GPIb as a novel antiplatelet agent for preventing further cardiovascular incidents in TD2M patients.

Plasma brain derived neurotrophic factor level as a modifying factor for trans fat intake and hypertension.

BACKGROUND & AIM: Long-term consumption of trans-fat has been linked with its incorporation in brain neural membrane that could lead into alteration of signalling pathways, including Brain Derived Neurotrophic Factor (BDNF). As an ubiquitous neurotrophin, BDNF is believed to play a role in the regulation of blood pressure yet prior studies shown conflicting results to its effect. Moreover, direct effect of trans fat intake to hypertension has not yet been elucidated. This study aimed to investigate the role of BDNF and its association between trans-fat intake and hypertension. MATERIALS & METHODS: We conducted a population study in Natuna Regency which once reportedly has the highest prevalence of hypertension from Indonesian National Health Survey. Subjects with hypertension and those without hypertension were recruited for the study. Demographic data, physical examination, and food recall were collected. The level of BDNF from all subjects were obtained through analysis of blood samples. RESULTS: A total of 181 participants were included in this study, comprising 134 (74%) hypertensive subjects and 47 (26%) normotensive subjects. Median of daily trans-fat intake of hypertensive subjects was higher compared to normotensive subjects (0,013 [0,0003-0,07] vs 0,010 [0,0006-0,06] % of total energy/day, p = 0,021). Interaction analysis showed significant results for plasma BDNF level in relationship of trans-fat intake and hypertension (p = 0,011). Trans-fat intake association to hypertension in overall subjects showed odds ratio (OR) of 1,85 95%CI 1,05-3,26 (p = 0,034), while in those with low-middle tercile BDNF level the OR was 3,35 95%CI 1,46-7,68 (p = 0,004). CONCLUSION: Plasma BDNF level has a modifying effect in the association between trans-fat intake and hypertension. Subjects with high trans-fat intake, while having low BDNF level, have the highest probability for hypertension.

A Novel Peptide Elabela is Associated with Hypertension-Related Subclinical Atherosclerosis.

INTRODUCTION: Elabela is a newly identified peptide which, alongside apelin, acts as an endogenous ligand that activates the angiotensin receptor-like 1 receptor. Previous studies have shown the association of elabela with hypertension, but information about the role of elabela in hypertension-related subclinical atherosclerosis is scarce. AIM: We aimed to determine the elabela levels in hypertensive patients and explore its association with subclinical atherosclerosis. METHODS: A total of 104 subjects with hypertension were included in the study. Elabela levels were measured using an enzyme-linked immunosorbent assay, by first extracting the peptide following the manufacturer's instructions. Subclinical atherosclerosis was assessed by measuring the carotid intima-media thickness (IMT) using ultrasound. RESULTS: Compared to stage 1, elabela levels decreased in stage 2 hypertension (0.23 [0.13, 0.45] ng/ml vs. 0.14 [0.09, 0.23] ng/ml; P = 0.000), and in the group with increased carotid IMT compared to normal IMT (0.24 [0.13, 0.38] ng/ml vs. 0.15 [0.10, 0.23] ng/ml; P = 0.005). Additionally, a linear correlation analysis showed that elabela had a significant negative correlation with systolic blood pressure (r = - 0.340, P = 0.000) and carotid IMT (r = - 0.213; P = 0.030). In multivariate analysis, lower elabela levels were associated with a higher cardiovascular risk group in this study (OR 5.0, 95% CI 1.8-13.5, P < 0.001). CONCLUSIONS: This study demonstrated for the first time that circulating elabela declined in a higher stage of hypertension and hypertensive patients with increased carotid IMT, implicating that elabela may be involved in the pathogenesis of hypertension-associated subclinical atherosclerosis.

Endothelin XVI.

Although 31 years have passed since the discovery of endothelin, that pioneering report, and the subsequent flood of influential studies elucidating its molecular and clinical details, have since paved the way for thousands of publications. They showed the promise of endothelin and the vast amount of work that remains to be done to fully unleash the potential this peptide possesses, both as a key physiological regulator and as a therapeutic target. Endothelin conferences and their proceedings have served as a host for many of these breakthrough studies, and in keeping with this fine tradition, Endothelin XVI will host novel research articles presented at the Sixteenth International Conference on Endothelin (ET-16) as its proceedings. On September 22-25, 2019, ET-16 was held at Kobe Port Oasis, Kobe, Japan, where numerous important discoveries were presented to the scientific community for the first time, many of which are compiled and published in this special issue. As the Editors of this special issue that comprises in-depth reviews, insightful editorials, and numerous original research articles discussing findings from various biomedical fields, we are extremely proud to present Endothelin XVI. We sincerely hope for the continued growth of this field for the benefit of the patients and the advancement of biomedical science.

May Measurement Month 2018: an analysis of blood pressure screening results from Indonesia.

Elevated blood pressure (BP) is a significant burden worldwide, leading to high cardio-cerebro-reno-vascular morbidity and mortality. For the second year of the May Measurement Month (MMM) campaign in Indonesia in 2018, we recruited 174 sites in 31 out of 34 provinces in Indonesia and screened through convenience sampling in public areas and rural primary health centres. Hypertension was defined as systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or both, or on the basis of receiving antihypertensive medication. Blood pressure was measured three times followed the standard global MMM protocol, multiple imputation was used to estimate the mean of the 2nd and 3rd BP readings if these were not recorded. A total of 91 222 individuals were screened, and after multiple imputations, 27 331 (30.0%) had hypertension. Of individuals not receiving antihypertensive medication, 14 367 (18.4%) were hypertensive. Among the 47.4% of hypertensive individuals on antihypertensive medication, 10 106 (78.0%) had uncontrolled BP. MMM17 and MMM18 were still the most extensive standardized screening campaigns for BP measurement in Indonesia. Compared to the previous study, the proportion with uncontrolled BP on medication was significantly higher and provided the substantial challenges in managing hypertension in the rural community.

The Sixteenth International Conference on Endothelin (ET-16), Kobe, 2019.

The Sixteenth International Conference on Endothelin (ET-16) was held September 22-25, 2019, in Kobe Port Oasis, Kobe, Japan, and co-chaired by Noriaki Emoto, MD, PhD, from Kobe Pharmaceutical University and Bambang Widyantoro, MD, PhD, from the University of Indonesia. As the sixteenth iteration of this biannual conference that has been held since 1988, ET-16 provided a platform for researchers of all generations from all parts of the world to present novel discoveries in the field of endothelin. ET-16 returned to Asia and to Kobe, Japan, after 6 years of alternating venues with North America and Europe, with over 100 participants attending, sharing, and discussing the newest findings on endothelin and endothelin receptor antagonists in science and medicine.

May Measurement Month 2017: an analysis of the blood pressure screening campaign results in Indonesia-South-East Asia and Australasia.

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. Our previous primary health surveys in 2013 and 2018 show that 25.8% to 34.1% of adults have raised BP, which is associated with cardiovascular, cerebrovascular, and renovascular morbidity and mortality. May Measurement Month (MMM) is a global initiative aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programmes worldwide. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2017. Blood pressure measurement, the definition of hypertension and statistical analysis followed the standard MMM protocol. We recruited 292 sites in all 34 provinces in Indonesia, and screened in public areas and offices as well as health centres. A total of 69 307 individuals were screened. After multiple imputation, 23 892 (34.5%) had hypertension. Of individuals not receiving antihypertensive medication, 20.0% were hypertensive. Among individuals receiving antihypertensive medication, 7885 (62.8%) had uncontrolled BP. MMM17 was the largest standardized screening campaign for BP measurement in our country. The proportion of individuals identified with hypertension and the percentage of those with uncontrolled BP on medication provide evidence of the substantial challenges in managing hypertension in the community. These results suggest that opportunistic screening can identify significant numbers of individuals with raised BP.

Attenuation of CHOP-mediated myocardial apoptosis in pressure-overloaded dominant negative p38α mitogen-activated protein kinase mice.

BACKGROUND/AIMS: Pressure overload stimulation is known to elicit disturbances in the endoplasmic reticulum (ER), which leads to ER stress (ERS). p38 mitogen-activated protein kinase (MAPK) plays an important role in mediating apoptotic processes, however, the roles of this kinase in activating ERS-initiated apoptosis in pressure-overloaded hearts are largely unknown. METHODS: We clarified the role of p38α MAPK in ERS-associated apoptosis by subjecting transgenic mice displaying cardiac specific dominant negative (DN) mutant p38α MAPK over-expression to seven day pressure overload. RESULTS: Seven days pressure overload resulted in the same extent of cardiac hypertrophy and ERS in the wild-type (WT) and DN p38α mice compared with the sham mice. It also activated inositol-requiring enzyme (Ire)-1α and its downstream molecule, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2 in the WT and DN p38α mice compared with the sham mice. Interestingly, increased myocardial apoptosis and the up-regulation of CCAAT/enhancer binding protein homology protein (CHOP) expression compared with those in the sham mice were found in the aortic-banded WT mice, but not in the DN p38α mice. CONCLUSION: Partial inhibition of p38α protein blocked the activation of CHOP-mediated apoptotic processes during pressure overload by partially inhibiting signaling from the Ire-1α/TRAF2 to its down-stream molecule, CHOP.

Sex differences play a role in cardiac endoplasmic reticulum stress (ERS) and ERS-initiated apoptosis induced by pressure overload and thapsigargin.

Excessive endoplasmic reticulum stress (ERS) triggers myocardial apoptosis. Sex differences appear to be an important determinant in the occurrence of stress and apoptosis through many pathways, but the roles of sex differences in the cardiac ERS and ERS-initiated apoptosis are largely unknown. In the present study, we investigated the in vivo role of sex differences in the cardiac ERS and apoptosis elicited by ascending aortic banding surgery or thapsigargin (Thap) injection using male and female C57BL/6 JAX mice. The surgery significantly increased the expression levels of cardiac glucose-regulated protein (GRP)78 and CCAAT/enhancer binding protein homology protein (CHOP) protein, increased the myocardial apoptosis and decreased the sarcoplasmic reticulum Ca(2+)-ATPase isoform (SERCA)2 immunoreactivity in the male mice relative to female mice. Furthermore, during ERS induction using Thap, myocardial apoptosis and the expression levels of cardiac GRP78, inositol-requiring enzyme (Ire)1α and tumor necrosis factor receptor-associated factor (TRAF)2 were significantly increased in male mice relative to female mice. Sex differences significantly affected the above results. Our data suggest that sex differences affected the response of myocardial tissues in dealing with cardiac ERS and further result of ERS, apoptosis, at least in part through the regulation of SERCA2, CHOP, Ire1α and TRAF2.

Knockout of endothelin-1 in vascular endothelial cells protects against insulin resistance induced by high-salt diet in mice.

The increased plasma Endothelin-1 (ET-1) level has been associated with development of insulin resistance in obese and hypertensive patients. However, the underlying mechanism remains elusive. Here we investigate the potential role of endothelial cell-derived ET-1 in mediating insulin resistance induced by high-salt diet. To address this issue, we used vascular endothelial cell-specific ET-1 knockout (VEETKO) mice and its littermates fed with a high-salt diet containing 8% NaCl for 3 weeks, and evaluated the metabolic parameters. High-salt diet increased systolic blood pressure similarly in both genotypes. We observed impairment of glucose tolerance in control mice despite comparable increase of serum insulin concentration with VEETKO mice. We further found that VEETKO mice showed preservation of circulating adiponectin level - an adipokine with insulin-sensitizing property - and prevention of the upregulation of the pro-inflammatory adipokine TNF-α, which lead towards better insulin sensitivity. These results provide evidence that blockade of endothelin signaling may be proven beneficial in preventing high-salt induced insulin resistance.

Partial inactivation of cardiac 14-3-3 protein in vivo elicits endoplasmic reticulum stress (ERS) and activates ERS-initiated apoptosis in ERS-induced mice.

BACKGROUND/AIMS: Excessive endoplasmic reticulum stress (ERS) triggers apoptosis in various conditions including diabetic cardiomyopathy and pressure overload-induced cardiac hypertrophy and heart failure. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis are largely unknown. METHODS: We investigated the roles of 14-3-3 protein in vivo during cardiac ERS and apoptosis induced by pressure overload or thapsigargin injection using transgenic (TG) mice that showed cardiac-specific expression of dominant negative (DN) 14-3-3eta. RESULTS: Cardiac positive apoptotic cells and the expression of glucose-regulated protein (GRP)78, inositol-requiring enzyme (Ire)1alpha, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2, CCAAT/enhancer binding protein homology protein (CHOP), caspase-12, and cleaved caspase-12 protein were significantly increased in the pressure-overload induced DN 14-3-3eta mice compared with that in the WT mice. Furthermore, thapsigargin injection significantly increased the expression of GRP78 and TRAF2 expression in DN 14-3-3eta mice compared with that in the WT mice. CONCLUSION: The enhancement of 14-3-3 protein may provide a novel protective therapy against cardiac ERS and ERS-initiated apoptosis, at least in part, through the regulation of CHOP and caspase-12 via the Ire1alpha/TRAF2 pathway.

Low blood pressure in endothelial cell-specific endothelin 1 knockout mice.

Endothelin (ET) 1 is a potent vasoconstrictor peptide produced by vascular endothelial cells and implicated in various pathophysiologic states involving abnormal vascular tone. Homozygous ET-1 null mice have craniofacial and cardiac malformations that lead to neonatal death. To study the role of ET-1 in adult vascular physiology, we generated a mouse strain (ET-1(flox/flox);Tie2-Cre mice) in which ET-1 is disrupted specifically in endothelial cells. ET-1 peptide levels in plasma, heart, lung, kidney, and brain homogenates were reduced by 65% to 80% in these mice. mRNA levels for ET receptors were unaltered except that the ET(A) receptor mRNA was upregulated in the heart. ET-1(flox/flox);Tie2-Cre mice had mean blood pressures 10 to 12 mm Hg lower than genetic controls. In contrast, the blood pressure of mice systemically heterozygous for the ET-1 null allele (ET-1(dlox/+) mice) was unchanged compared with wild-type littermates. Despite the lower basal blood pressure, acute pharmacological responses to angiotensin II, captopril, phenylephrine, bradykinin, N(G)-nitro-L-arginine methyl ester, and exogenous ET-1 were normal in ET-1(flox/flox);Tie2-Cre mice. These results support an essential role of endothelial-derived ET-1 in the maintenance of basal vascular tone and blood pressure. Normal pharmacological responses of ET-1(flox/flox);Tie2-Cre mice suggest that the renin-angiotensin system, the adrenergic system, and NO are not significantly altered by endothelial ET-1. Taken in conjunction with other lines of genetically altered mice, our results provide evidence for a paracrine vasoregulatory pathway mediated by endothelial cell-derived ET-1 acting on the vascular smooth muscle ET(A) receptor.

Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition.

BACKGROUND: Persistently high plasma endothelin-1 (ET-1) levels in diabetic patients have been associated with the development of cardiac fibrosis, which results from the deposition of extracellular matrix and fibroblast recruitment from an as-yet unknown source. The underlying mechanism, however, remains elusive. Here, we hypothesize that ET-1 might contribute to the accumulation of cardiac fibroblasts through an endothelial-to-mesenchymal transition in diabetic hearts. METHODS AND RESULTS: We induced diabetes mellitus in vascular endothelial cell-specific ET-1 knockout [ET-1(f/f);Tie2-Cre (+)] mice and their wild-type littermates using the toxin streptozotocin. Gene expression and histological and functional parameters were examined at 8, 24, and 36 weeks after the induction of diabetes mellitus. Diabetes mellitus increased cardiac ET-1 expression in wild-type mice, leading to mitochondrial disruption and myofibril disarray through the generation of superoxide. Diabetic mice also showed impairment of cardiac microvascularization and a decrease in cardiac vascular endothelial growth factor expression. ET-1 further promotes cardiac fibrosis and heart failure through the accumulation of fibroblasts via endothelial-to-mesenchymal transition. All of these features were abolished in ET-1(f/f);Tie2-Cre (+) hearts. Targeted ET-1 gene silencing by small interfering RNA in cultured human endothelial cells ameliorated high glucose-induced phenotypic transition and acquisition of a fibroblast marker through the inhibition of transforming growth factor-beta signaling activation and preservation of the endothelial cell-to-cell contact regulator VE-cadherin. CONCLUSIONS: These results provide new insights suggesting that diabetes mellitus-induced cardiac fibrosis is associated with the emergence of fibroblasts from endothelial cells and that this endothelial-to-mesenchymal transition process is stimulated by ET-1. Targeting endothelial cell-derived ET-1 might be beneficial in the prevention of diabetic cardiomyopathy.

Attenuation of Doxorubicin-induced cardiomyopathy by endothelin-converting enzyme-1 ablation through prevention of mitochondrial biogenesis impairment.

Doxorubicin is an effective antineoplastic drug; however, its clinical benefit is limited by its cardiotoxicity. The inhibition of mitochondrial biogenesis is responsible for the pathogenesis of doxorubicin-induced cardiomyopathy. Endothelin-1 is a vasoconstrictive peptide produced from big endothelin-1 by endothelin-converting enzyme-1 (ECE-1) and a multifunctional peptide. Although plasma endothelin-1 levels are elevated in patients treated with doxorubicin, the effect of ECE-1 inhibition on doxorubicin-induced cardiomyopathy is not understood. Cardiomyopathy was induced by a single IP injection of doxorubicin (15 mg/kg). Five days after treatment, cardiac function, histological change, and mitochondrial biogenesis were assessed. Echocardiography revealed that cardiac systolic function was significantly deteriorated in doxorubicin-treated wild-type (ECE-1(+/+)) mice compared with ECE-1 heterozygous knockout (ECE-1(+/-)) mice. In histological analysis, cardiomyocyte size in ECE-1(+/-) mice was larger, and cardiomyocyte damage was less. In ECE-1(+/+) mice, tissue adenosine triphosphate content and mitochondrial superoxide dismutase were decreased, and reactive oxygen species generation was increased compared with ECE-1(+/-) mice. Cardiac mitochondrial deoxyribonucleic acid copy number and expressions of key regulators for mitochondrial biogenesis were decreased in ECE-1(+/+) mice. Cardiac cGMP content and serum atrial natriuretic peptide concentration were increased in ECE-1(+/-) mice. In conclusion, the inhibition of ECE-1 attenuated doxorubicin-induced cardiomyopathy by inhibiting the impairment of cardiac mitochondrial biogenesis. This was mainly induced by decreased endothelin-1 levels and an enhanced atrial natriuretic peptide-cGMP pathway. Thus, the inhibition of ECE-1 may be a new therapeutic strategy for doxorubicin-induced cardiomyopathy.

Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation.

AIMS: Although endothelin-1 (ET-1) has been suggested to contribute to the pathogenesis of neointima formation and atherosclerosis, the individual roles of ET-1 derived from certain cell types in this disease remain unclear. In this study, we determined the role of vascular endothelial ET-1 on vascular inflammation and neointima formation using vascular endothelial ET-1-knockout [ET-1(f/f); Tie2-Cre (+)] mice. METHODS AND RESULTS: Intimal hyperplasia was induced by complete ligation of the left carotid artery in 12-week-old male ET-1(f/f);Tie2-Cre (+) mice (n = 35) and the wild-type (WT) littermates (n = 34). Following this intervention, neointima formation was reduced in ET-1(f/f);Tie2-Cre (+) mice compared with the WT mice, independent of the difference in blood pressure. This reduction was associated with a decrease in inflammatory cell recruitment to the vessel wall, which was accompanied by reduced expression levels of endothelial adhesion molecules as well as chemokines and a decrease in vascular smooth muscle cell proliferation. CONCLUSION: The results of our study provide direct evidence for the role of vascular endothelial ET-1 in mediating vascular inflammation and neointima formation following vascular injury in addition to promoting vasoconstriction and cell proliferation. Furthermore, this study suggests a strategy for the efficient design of ET receptor antagonists with targeted inhibition of ET-1 signalling in vascular endothelial cells.