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.

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.

Work stress and changes in heart rate variability among employees after first acute coronary syndrome: a hospital-based longitudinal cohort study.

Background: Work stress is considered as a risk factor for coronary heart disease, but its link with heart rate variability (HRV) among heart attack survivors is unknown yet. The aim of this study was to investigate associations between baseline work stress and the changes of HRV over one-year after onset of acute coronary syndrome (ACS). Methods: Hundred and twenty-two patients with regular paid work before their first ACS episode were recruited into this hospital-based longitudinal cohort study. During hospitalization (baseline), all patients underwent assessments of work stress by job strain (JS) and effort-reward imbalance (ERI) models, and were assigned into low or high groups; simultaneously, sociodemographic and clinical data, as well depression, anxiety, and job burnout, were collected. Patients were followed up 1, 6, and 12 months after discharge, with HRV measurements at baseline and each follow-up point. Generalized estimating equations were used to analyze the effects of baseline work stress on HRV over the following 1 year. Results: After adjusting for baseline characteristics and clinical data, anxiety, depression, and burnout scores, high JS was not associated with any HRV measures during follow-up (all p > 0.10), whereas high ERI was significantly related to slower recovery of 5 frequency domain HRV measures (TP, HF, LF, VLF, and ULF) (all p < 0.001), and marginally associated with one time domain measure (SDNN) (p = 0.069). When mutually adjusting for both work stress models, results of ERI remained nearly unchanged. Conclusion: Work stress in terms of ERI predicted lower HRV during the one-year period after ACS, especially frequency domain measures.

Longitudinal Associations of Work Stress with Changes in Quality of Life among Patients after Acute Coronary Syndrome: A Hospital-Based Study.

(1) Background: Targeting a sample of Chinese employees in this study, the correlation of work stress with changes in quality of life (QoL) was explored subsequent to acute coronary syndrome (ACS). (2) Methods: Patients suffering from the first ACS episode, with regular paid work before ACS, were eligible for this one-year longitudinal study. Effort-reward imbalance (ERI), together with job strain (JS) models, were employed to evaluate work stress before discharge, and QoL prior to discharge (baseline), as well as at 1, 6, and 12 months following discharge, were measured using the 8-Items Short Form (SF-8), in addition to the Seattle Angina Questionnaire (SAQ). Moreover, generalized estimating equations were used to determine the relationship of work stress to longitudinal QoL variations. (3) Results: After adjusting for covariates, high work stress at the baseline measured by JS was associated with the slow recovery of both mental health (p < 0.01) and physical health (p < 0.05) in SF-8, while ERI-measured work stress was related to slower improvement in SF-8 physical health (p < 0.001), SAQ-angina stability (AS) (p < 0.05), SF-8 mental health (p < 0.001), and SAQ-angina frequency (AF) (p < 0.05). After mutual adjustment for JS and ERI, high work stress as assessed by JS displayed no correlation with any QoL alteration (all p > 0.05), whereas ERI-determined work stress at a high level still presented a relationship to slow improvement in SF-8 physical health, SAQ-AS, SF-8 mental health, and SAQ-AF (all p < 0.05). (4) Conclusion: Work stress was associated with slow recovery of QoL in patients with ACS across one year. For ACS patients, ERI was a stronger predictor of QoL variations than JS.

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.