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Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure. Cardiac fibrosis is a hallmark of heart failure. Here the authors use single-cell RNA-sequencing, spatial transcriptomics, and genetic manipulations, to show that Htra3 regulates cardiac fibrosis by keeping fibroblasts quiescent and by degrading TGF-beta.

Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes. The mechanisms underlying the transition from cardiac hypertrophy to heart failure following pressure overload are incompletely understood. Here the authors identify the gene programs encoding the morphological and functional characteristics of cardiomyocytes during the transition from early hypertrophy to heart failure via single-cell transcriptomics, establishing a key role for p53 signalling.

Although inflammation plays critical roles in the development of atherosclerosis, its regulatory mechanisms remain incompletely understood. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, we show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulate in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by genetically silencing PRDM16, a key regulator to beiging, exacerbates inflammation and vascular remodeling following injury. Conversely, activation of PVAT beiging attenuates inflammation and pathological vascular remodeling. Single-cell RNA sequencing reveals that beige adipocytes abundantly express neuregulin 4 ( Nrg4 ) which critically regulate alternative macrophage activation. Importantly, significant beiging is observed in the diseased aortic PVAT in patients with acute aortic dissection. Taken together, vascular injury induces the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitates alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrates the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, the authors show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response as a protective mechanism.

Epidemiological evidence on the relationship between lipid profile and cardiovascular disease (CVD) events in young adults remains insufficient. Thus, we sought to explore the association of lipid profile with subsequent CVD among young adults. Medical records of 1,451,997 young adults (20 to 49 years old) without prior history of CVD and not taking lipid lowering medications were extracted from the Japan Medical Data Center, a nationwide epidemiological database. We conducted multivariable Cox regression analyses to identify the association between lipid profile and the subsequent risk of CVD and used multiple imputation for missing data on body mass index, waist circumference, hypertension, diabetes mellitus, and cigarette smoking in our database. The mean age was 39.0 ± 7.4 years, and 58.5% were men. After a mean follow-up of 1,148 ± 893 days, myocardial infarction, angina pectoris, stroke, and heart failure developed in 1,638 (0.1%), 15,887 (1.1%), 5,593 (0.4%), and 14,351 (1.0%) subjects, respectively. Multivariable Cox regression analyses including covariates after multiple imputation for missing values demonstrated that LDL-C ≥ 140 mg/dL, HDL-C < 40 mg/dL, and triglycerides ≥ 150 mg/dL were independently associated with the incidence of myocardial infarction, angina pectoris, and heart failure. However, they were not associated with the incidence of stroke. Multivariable Cox regression analyses including the number of abnormal lipid profiles and covariates showed that the incidence of myocardial infarction, angina, and heart failure increased stepwise with the number of abnormal lipid profiles. However, the number of abnormal lipid profiles was not associated with the subsequent risk of stroke. In conclusion, the comprehensive analysis of a nationwide epidemiological database demonstrated a close relationship between lipid profile and subsequent CVD, suggesting the importance of maintaining an optimal lipid profile for the primary prevention of CVD in young generations.

One of the major global health and welfare issues is the treatment of obesity and associated metabolic disorders, such as type 2 diabetes mellitus and nonalcoholic fatty liver disease. Obesity, caused by the excessive accumulation of triglycerides in adipose tissues, induces adipocyte dysfunction, followed by inflammation, in adipose tissues and lipotoxicity in nonadipose tissues. Several studies have shown that obesity and glucose homeostasis are influenced by sphingolipid mediators, including ceramide and sphingosine 1-phosphate (S1P). Cellular accumulation of ceramide impairs pancreatic β-cell survival, confers insulin resistance in the liver and the skeletal muscle, and deteriorates adipose tissue inflammation via unknown molecular mechanisms. The roles of S1P are more complicated, because there are five cell-surface S1P receptors (S1PRs: S1P1–5) which have altered functions, different cellular expression patterns, and inapparent intracellular targets. Recent findings, including those by our group, support the notable concept that the pharmacological activation of S1P1 or S1P3 improves obesity and associated metabolic disorders, whereas that of S1P2 has the opposite effect. In addition, the regulation of S1P production by sphingosine kinase (SphK) is an essential factor affecting glucose homeostasis. This review summarizes the current knowledge on SphK/S1P/S1PR signaling in and against obesity, insulin resistance, and associated disorders.

The lasso peptide MS-271 is a ribosomally synthesized and post-translationally modified peptide (RiPP) consisting of 21 amino acids with D-tryptophan at the C -terminus, and is derived from the precursor peptide MslA. MslH, encoded in the MS-271 biosynthetic gene cluster ( msl ), catalyzes the epimerization at the Cα center of the MslA C -terminal Trp21, leading to epi -MslA. The detailed catalytic process, including the catalytic site and cofactors, has remained enigmatic. Herein, based on X-ray crystallographic studies in association with MslA core peptide analogues, we show that MslH is a metallo-dependent peptide epimerase with a calcineurin-like fold. The crystal structure analysis, followed by site-directed mutagenesis, docking simulation, and ICP-MS studies demonstrate that MslH employs acid/base chemistry to facilitate the reversible epimerization of the C- terminal Trp21 of MslA, by utilizing two pairs of His/Asp catalytic residues that are electrostatically tethered to a six-coordination motif with a Ca(II) ion via water molecules. MslH, encoded in the MS-271 biosynthetic gene cluster, catalyzes the epimerization at the Cα center of the MslA C-terminal Trp21, however, the detailed catalytic process was unknown. Here, the authors report MslH is a metallo-dependent peptide epimerase with a calcineurin-like fold.

Background In the wake of the coronavirus disease 2019 (COVID-19) pandemic, people need to practice social distancing in order to protect themselves from SARS-CoV-2 infection. In such stressful situations, remote cardiac rehabilitation (CR) might be a viable alternative to the outpatient CR program. Methods We prospectively investigated patients hospitalized for heart failure (HF) with a left ventricular ejection fraction of < 50%. As for patients who participated in the remote CR program, telephone support was provided by cardiologists and nurses who specialized in HF every 2 weeks after discharge. The emergency readmission rate within 30 days of discharge was compared among the outpatient CR, remote CR, and non-CR groups, and the EQ-5D score was compared between the outpatient CR and remote CR groups. Results The participation rate of HF patients in our remote CR program elevated during the COVID-19 pandemic. As observed in the outpatient CR group ( n = 69), the emergency readmission rate within 30 days of discharge was lower in the remote CR group ( n = 30) than in the non-CR group ( n = 137) ( P = 0.02). The EQ-5D score was higher in the remote CR group than in the outpatient CR group ( P = 0.03) 30 days after discharge. Conclusions Remote CR is as effective as outpatient CR for improving the short-term prognosis of patients hospitalized for heart failure post-discharge. This suggests that the remote CR program can be provided as a good alternative to the outpatient CR program.

Serum uric acid (SUA) was reported to be associated with incident cardiovascular disease (CVD). However, the relationship between SUA and CVD among young adults has not been clarified yet. In this study, we aimed to identify the association of medication naïve SUA with incident CVD including myocardial infarction (MI), stroke, heart failure (HF) and atrial fibrillation (AF) using a nationwide epidemiological database. We analyzed 353,613 participants aged 20–49 years, who were not taking UA lowering medications, and had no prevalent history of cardiovascular disease (CVD) using a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2018. Median [interquartile range] age was 40 [34–44] years, and 46.9% were men. Over a mean follow-up of 1,176±876 days, 391 (0.1%) incident MI, 1,308 (0.4%) incident stroke, 3,374 (1.0%) incident HF, and 684 (0.2%) incident AF events occurred. Kaplan-Meier curves and the log-rank test showed that there was a significant difference in incident MI, stroke, HF, and AF among the groups based on SUA tertile (all log-rank p< 0.001). Multivariable Cox regression analysis showed that the upper tertile of SUA (SUA ≥ 5.7 mg/dL) was associated with higher incidence of MI (HR 1.45, 95% CI 1.00-2.10), HF (HR 1.13, 95% CI 1.01-1.28), and AF (HR 1.35, 95% CI 1.02-1.78) compared with the first tertile of SUA (SUA < 4.4 mg/dL). SUA as continuous variable was independently associated with incident MI (HR 1.10, 95% CI 1.00-1.20), stroke (HR 1.06, 95% CI 1.00-1.11), HF (HR 1.07, 95% CI 1.03-1.10), and AF (HR 1.11, 95% CI 1.04-1.19). SUA ≥ 7.0 mg/dL was independently associated with incident HF (HR 1.24, 95% CI 1.12-1.38). In conclusion, higher SUA was associated with increased incidence of CVD events in individuals aged< 50 years, suggesting the potential significance of the optimal UA control for the primary CVD prevention even in young adults.

Background There have been scarce data comparing cardiovascular outcomes between individual sodium-glucose cotransporter-2 (SGLT2) inhibitors. We aimed to compare the subsequent cardiovascular risk between individual SGLT2 inhibitors. Methods We analyzed 25,315 patients with diabetes mellitus (DM) newly taking SGLT2 inhibitors (empagliflozin: 5302, dapagliflozin: 4681, canagliflozin: 4411, other SGLT2 inhibitors: 10,921). We compared the risks of developing heart failure (HF), myocardial infarction (MI), angina pectoris (AP), stroke, and atrial fibrillation (AF) between individual SGLT2 inhibitors. Results Median age was 52 years, and 82.5% were men. The median fasting plasma glucose and HbA1c levels were 149 (Q1-Q3:127–182) mg/dL and 7.5 (Q1-Q3:6.9–8.6) %. During a mean follow-up of 814 ± 591 days, 855 HF, 143 MI, 815 AP, 340 stroke, and 139 AF events were recorded. Compared with empagliflozin, the risk of developing HF, MI, AP, stroke, and AF was not significantly different in dapagliflozin, canagliflozin, and other SGLT inhibitors. For developing HF, compared with empagliflozin, hazard ratios of dapagliflozin, canagliflozin, and other SGLT2 inhibitors were 1.02 (95% confidence interval [CI] 0.81–1.27), 1.08 (95% CI 0.87–1.35), and 0.88 (95% CI 0.73–1.07), respectively. Wald tests showed that there was no significant difference in the risk of developing HF, MI, AP, stroke, and AF among individual SGLT2 inhibitors. We confirmed the robustness of these results through a multitude of sensitivity analyses. Conclusion The risks for subsequent development of HF, MI, AP, stroke, and AF were comparable between individual SGLT2 inhibitors. This is the first study comparing the wide-range cardiovascular outcomes of patients with DM treated with individual SGLT2 inhibitors using large-scale real-world data.