孟刘坤
中国医学科学院阜外医院 心血管外科
The gut microbiome's imbalance has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), yet the contribution of the gut mycobiome remains largely unclear. This study delineates the gut mycobiome profile in PAH and examines its interplay with the bacterial microbiome alterations. Fecal samples from monocrotaline-induced PAH rats and matched controls were subjected to internal transcribed spacer 1 (ITS1) sequencing for fungal community assessment and 16S ribosomal RNA (rRNA) gene sequencing for bacterial community characterization. Comparative analysis revealed no significant disparities in the overall mycobiome diversity between the PAH and control groups. However, taxonomic profiling identified differential mycobiome compositions, with the PAH group exhibiting a significant enrichment of genera such as Wallemia, unidentified_Branch02, Postia, Malassezia, Epicoccum, Cercospora, and Alternaria. Conversely, genera Xeromyces, unidentified_Plectosphaerellaceae, and Monilia were more abundant in the controls. Correlations of Malassezia and Wallemia abundance with hemodynamic parameters were observed. Indications of bidirectional fungal-bacterial community interactions were also noted. This investigation reveals distinct gut mycobiome alterations in PAH, which are intricately associated with concurrent bacterial microbiome changes, suggesting a possible contributory role of gut fungi in PAH pathophysiology. These findings underscore the potential for novel gut mycobiome-targeted therapeutic interventions in PAH management.
Biomedicines 2024
Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular disease characterized by increased pulmonary vascular resistance, pulmonary vasoconstriction, and right ventricular hypertrophy. Recent developments in genomics and metabolomics have gradually revealed the roles of the gut microbiota (GM) and its metabolites in cardiovascular diseases. Accumulating evidence reveals that the GM plays important roles in the occurrence and development of PAH. Gut microbiota dysbiosis directly increases the gut permeability, thereby facilitating pathological bacterial translocation and allowing translocation of bacterial products such as lipopolysaccharides from the gut into circulation. This process aggravates pulmonary perivascular inflammation and exacerbates PAH development through the endothelial-mesenchymal transition. Additionally, a shift in the composition of PAH also affects the gut metabolites. Changes in gut metabolites, such as decreased short-chain fatty acids, increased trimethylamine N-oxide, and elevated serotonin, contribute to pulmonary perivascular inflammation and pulmonary vascular remodeling by activating several signaling pathways. Studies of the intestinal microbiota in treating pulmonary hypertension have strengthened linkages between the GM and PAH. Probiotic therapy and fecal microbiota transplantation may supplement existing PAH treatments. In this article, we provide new insight for diagnosing, preventing and treating PAH by adding to the current knowledge of the intestinal flora mechanisms and its metabolites efficacy involved in PAH.
Nutrients 2022
Bone morphogenetic protein (BMP) signaling is commonly suppressed in patients with pulmonary arterial hypertension (PAH), but the compensatory mechanism of BMP signaling suppression is incompletely elucidated. This study aimed to investigate the role of PRDC, an antagonist of BMPs, in PAH and the underlying mechanism. Human lungs were collected and rat PAH was induced (monocrotaline, 60 mg/kg). BMP cascade and PRDC were detected in lungs and distal pulmonary artery smooth muscle cells (dPASMCs). In vitro cell experiments and in vivo supplementation of PRDC in hypertensive rats were subsequently performed. PRDC and BMP cascade all decreased in human and rat hypertensive lungs. Cell experiments confirmed that BMP2/4 inhibited dPASMCs proliferation by increasing cell cycle inhibitors (p21, p27), prevented dPASMCs migration by down-regulating MMP2/9 and up-regulating TIMP1/2 expression, and promoted dPASMCs apoptosis by up-regulating Bax, caspase3/9 and down-regulating Bcl-2 expression, as well as enhancing caspase3/7 activity, while, PRDC reversed the effects of BMP2/4 on dPASMCs proliferation, migration and apoptosis. In vivo trial found that PRDC supplementation deteriorated rat PAH in terms of pulmonary hemodynamics, vasculopathies and right ventricle hypertrophy. Taken together, compensatory decrease of PRDC in hypertensive lungs theoretically slow down the natural course of PAH, suggesting its therapeutic potential in PAH.
International journal of biological sciences 2022
Increased levels of free fatty acid (FFA)-induced endothelial dysfunction play an important role in the initiation and development of atherosclerosis. Feprazone is a nonsteroidal anti-inflammatory compound. However, the beneficial effects of feprazone on FFA-induced endothelial dysfunction have not been reported before. In the current study, we found that treatment with feprazone ameliorated FFA-induced cell death of human aortic endothelial cells (HAECs) by restoring cell viability and reducing the release of lactate dehydrogenase (LDH). Importantly, we found that treatment with feprazone ameliorated FFA-induced oxidative stress by reducing the production of mitochondrial reactive oxygen species (ROS). In addition, feprazone prevented FFA-induced expression and secretion of proinflammatory cytokines and chemokines, such as chemokine ligand 5 (CCL5), interleukin-6 (IL-6), and interleukin-8 (IL-8). We also found that feprazone decreased the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Interestingly, we found that feprazone reduced the expression of cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1). Our results also demonstrate that feprazone prevented FFA-induced activation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa-B (NF-κB) signaling pathway. These findings suggest that feprazone might serve as a potential agent for the treatment of atherosclerosis by improving the endothelial function.
ACS omega 2021
Pulmonary arterial hypertension (PAH) secondary to congenital heart disease (CHD-PAH) with systemic-to-pulmonary shunt (SPS) is characterized by proliferative vascular remodeling. Capillary morphogenesis gene-2 (CMG2) plays a key role in cell proliferation and apoptosis. This study aimed to determine the role of CMG2 in the pathogenesis of SPS-induced PAH. CMG2 levels were significantly downregulated in pulmonary arterioles from patients with Eisenmenger syndrome and rats with SPS-induced PAH. CMG2 was highly expressed in several cells including human pulmonary arterial smooth muscle cells (HPASMCs). CMG2-/- rats exhibited more severe PAH and pulmonary vascular remodeling than wild-type rats when exposed to SPS for 8 weeks. Overexpression of CMG2 significantly inhibited proliferation and promoted apoptosis of HPASMCs, while knockdown of CMG2 promoted cell proliferation and inhibited cell apoptosis. Next-generation sequencing and subsequent validation results suggested that PI3K-AKT was the most prominent signaling pathway regulated by differentially expressed genes (DEGs) in CMG2-/- rat lungs. Our work identified a novel role for CMG2 in SPS-induced PAH based on the findings that CMG2 deficiency exacerbates SPS-induced vascular remodeling in the development of PAH, indicating that CMG2 might act as a potential target for the treatment of CHD-PAH.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2021
BACKGROUND:Myocardial bridging (MB) is commonly treated in patients with hypertrophic cardiomyopathy. However, whether and how MB should be treated in patients with hypertrophic obstructive cardiomyopathy (HOCM) who underwent septal myectomy remain unclear.METHODS:A total of 823 adults with HOCM who underwent septal myectomy at the Fuwai Hospital from 2011 to 2017 were retrospectively studied.RESULTS:Overall, 31 events occurred: 24 patients died and 7 had nonfatal myocardial infarction (MI). The 3-year cumulative event-free survival of all-cause death (97.9% vs. 100% vs. 100% vs. 98.4%, p = .89) and cardiovascular death (98.3% vs. 100% vs. 100% vs. 98.4%, p = .63) were similar among the four groups (non-MB, coronary artery bypass grafting [CABG], unroofing, untreated, respectively). However, the 3-year cumulative event-free survival of nonfatal MI (100% vs. 97.5% vs. 98.0% vs. 89.9%, p < .001) and combined endpoints (97.9% vs. 97.5% vs. 98.0% vs. 88.4%, p = .02) were significantly lowest in untreated MB (non-MB, CABG, unroofing, untreated, respectively). Cox regression analysis indicated that untreated MB was a significant independent predictor of combined endpoints (hazard ratio: 4.06, 95% confidence interval: 1.60-10.32, p < .001). Moreover, 49 patients underwent coronary artery computed tomography 1 year after surgery. The patency rate of the saphenous vein graft was significantly higher than that of the left internal mammary artery (13.3% vs. 84.2%, p < .001). No MB was detected in the unroofing group.CONCLUSIONS:Surgical MB treatment could be beneficial and performed safely during septal myectomy. Myocardial unroofing is the recommended treatment for MB, and unroofing when technically possible may be preferable for long-term outcomes.
Journal of cardiac surgery 2021
Background Heterozygous mutation in BMP (bone morphogenetic protein) receptor 2 is rare, but BMP cascade suppression is common in congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH); however, the underling mechanism of BMP cascade suppression independent of BMP receptor 2 mutation is unknown. Methods and Results Pulmonary hypertensive status observed in CHD-PAH was surgically reproduced in rats. Gremlin-1 expression was increased, but BMP cascade was suppressed, in lungs from CHD-PAH patients and shunted rats, whereas shunt correction retarded these trends in rats. Immunostaining demonstrated increased gremlin-1 was mainly in the endothelium and media of remodeled pulmonary arteries. However, mechanical stretch time- and amplitude-dependently stimulated gremlin-1 secretion and suppressed BMP cascade in distal pulmonary arterial smooth muscle cells from healthy rats. Under static condition, gremlin-1 significantly promoted the proliferation and inhibited the apoptosis of distal pulmonary arterial smooth muscle cells from healthy rats via BMP cascade. Furthermore, plasma gremlin-1 closely correlated with hemodynamic parameters in CHD-PAH patients and shunted rats. Conclusions Serving as an endogenous antagonist of BMP cascade, the increase of gremlin-1 in CHD-PAH may present a reasonable mechanism explanation for BMP cascade suppression independent of BMP receptor 2 mutation.
Journal of the American Heart Association 2020
BACKGROUND:The prevalence of obstructive sleep apnoea (OSA) is high in patients with hypertrophic cardiomyopathy. The effect of septal myectomy on OSA is not clear. This study aimed to examine the association between hypertrophic obstructive cardiomyopathy and OSA before and after septal myectomy.METHOD:We included 85 consecutive patents with a confirmed diagnosis of hypertrophic obstructive cardiomyopathy who underwent septal myectomy. Polysomnography was performed in all patients before and 3 months after the surgery.RESULTS:Of the 85 patients, 49 (58%) were diagnosed with OSA. Patients with OSA were significantly older than those without OSA. The incidence of atrial fibrillation significantly increased during the perioperative period in patients with OSA (p = 0.03). The severity of OSA significantly increased 3 months after surgery, as determined by the apnoea-hypopnoea index (AHI; p < 0.001), obstructive apnoea index (p = 0.024), and hypopnoea index (p = 0.003), whereas central apnoea index was decreased (p = 0.008). In the multivariate linear regression analysis, mean oxygen desaturation and time% with SpO2 <90% during sleep before surgery were significantly associated with increased AHI, independently of body mass index and sex (p = 0.026 and p = 0.007, respectively; adjusted R2 = 0.365).CONCLUSIONS:The severity of OSA significantly increased 3 months after septal myectomy as determined by AHI, obstructive apnoea index, and hypopnoea index. Mean oxygen saturation and time% with SpO2 <90% during sleep before surgery were independently associated with the increase of AHI. However, the specific mechanism of such deterioration of OSA after septal myectomy needs to be determined in detail.
Heart, lung & circulation 2020
AIM:Proteins mainly expressed in normal lungs and significantly changed in lungs exposed to systemic-to-pulmonary shunts might be promising targets for pulmonary arterial hypertension induced by congenital heart diseases (PAH/CHD). This study aimed to investigate the potential role of differential screening-selected gene aberrative in neuroblastoma (DAN) in PAH/CHD.METHODS:PAH was surgically induced by the combined surgery (right pulmonary artery ligation and left cervical systemic-to-pulmonary shunt) in Sprague-Dawley (SD) rats. Exogenous DAN was supplemented by osmotic minipumps.RESULTS:Firstly, DAN was significantly decreased in patients with severe PAH/CHD and negatively correlated with pulmonary hemodynamic indices derived from right cardiac catheterization. Secondly, pulmonary hypertensive status and apparent pulmonary vasculopathies of PAH/CHD were surgically reproduced in SD rats. Real time-PCR and Western blot analysis revealed that DAN mRNA and protein levels decreased in lungs exposed to systemic-to-pulmonary shunts, and immunofluorescence staining found that DAN was highly expressed in pulmonary arteries of normal lungs but seldom detected in severely remodelling pulmonary arteries, furthermore, plasma levels of DAN in shunted-rats manifested a time-depended decrease and negatively correlated with pulmonary hemodynamic indices. Thirdly, DAN specially reversed the anti-proliferative and pro-apoptotic effects of bone morphogenetic protein 2/4 (BMP2/4) on pulmonary arterial smooth muscle cells via BMP2/4-BMPR2-Smad1/5/8-Id1 signalling pathway. Furthermore, continuous supplementation of exogenous DAN protein increased the extent of shunt-associated PAH.CONCLUSION:Compensatory decrease of DAN in hypertensive lungs may retard the deterioration of shunt-associated PAH, at least in part, by antagonizing BMP signalling pathway. Furthermore, DAN might be a potential biomarker for PAH/CHD.
Acta physiologica (Oxford, England) 2019
BACKGROUND:Obstructive sleep apnea (OSA) prevalence is high among patients with hypertrophic cardiomyopathy (HCM). OSA can cause increase in carotid intima-media thickness (CIMT) in the general population. However, whether this phenomenon is applicable to patients with HCM is unclear.METHODS:A total of 130 consecutive patients with a confirmed diagnosis of hypertrophic obstructive cardiomyopathy (HOCM) at Fuwai Hospital between September 2017 and May 2018 were analyzed.RESULTS:72 patients (55.4%) were diagnosed with OSA. Patients with OSA were older. Compared to those in patients without OSA, the left, right, and mean CIMTs were significantly increased in patients with OSA. In the multiple linear regression model, age (β = 0.341, p < 0.001), apnea-hypopnea index (AHI) (β = 0.421, p < 0.001), and fasting glucose level (β = 0.167, p < 0.03) were independently associated with mean CIMT increase (adjusted R2 = 0.458, p < 0.001). In the receiver operating characteristic curve analysis, the area under the curve for CIMT was 0.813 (95% CI, 0.717-0.909, p < 0.001) with a sensitivity and specificity of 0.84 and 0.70 for unexplained syncope, respectively. In the multivariate logistic regression model, we found that the mean CIMT (OR = 10.4, 95% CI = 3.16-34.11, p < 0.001), left ventricular ejection fraction (LVEF) (OR = 0.90, 95% CI = 0.83-0.99, p = 0.03), and amaurosis (OR = 5.07, 95% CI = 1.47-17.49, p = 0.01) were independently associated with unexplained syncope occurrence.CONCLUSIONS:In patients with HOCM, CIMT increased with OSA severity. Age, AHI, and fasting plasma glucose level were independently associated with mean CIMT increase. Moreover, amaurosis, LVEF, and higher mean CIMT were independently associated with unexplained syncope in patients with HOCM.
Respiratory medicine 2019
