李昊
北京大学第三医院 血管医学研究所
Rationale: The progressive disruption of extracellular matrix (ECM) proteins, particularly early elastin fragmentation followed by abnormalities in collagen fibril organization, are key pathological processes that contribute to dissecting abdominal aortic aneurysm (AAA) pathogenesis. Lysyl hydroxylase 1 (LH1) is essential for type I/III collagen intermolecular crosslinking and stabilization. However, its function in dissecting AAA has not been explored. Here, we investigated whether LH1 is significantly implicated in dissecting AAA progression and therapeutic intervention. Methods and Results: Sixteen-week-old male LH1-deficient and wild-type (WT) mice on the C57Bl/6NCrl background were infused with angiotensin II (Ang II, 1000 ng/kg per minute) via subcutaneously implanted osmotic pumps for 4 weeks. Ang II increased LH1 levels in the abdominal aortas of WT mice, whereas mice lacking LH1 developed dissecting AAA. To evaluate the related mechanism, we performed whole-transcriptomic analysis, which demonstrated that LH1 deficiency aggravated gene transcription alterations; in particular, the expression of thrombospondin-1 was markedly upregulated in the aortas of LH1-deficient mice. Furthermore, targeting thrombospondin-1 with TAX2 strongly inhibited the proinflammatory process, matrix metalloproteinase (MMP) activity and vascular smooth muscle cells (VSMCs) apoptosis, ultimately decreasing the incidence of dissecting AAA. Restoration of LH1 protein expression in LH1-deficient mice by intraperitoneal injection of an adeno-associated virus normalized thrombospondin-1 levels, subsequently alleviating dissecting AAA formation and preserving aortic structure and function. Consistently, in human AAA specimens, decreased LH1 expression was associated with increased thrombospondin-1 levels. Conclusions: LH1 deficiency contributes to dissecting AAA pathogenesis, at least in part, by upregulating thrombospondin-1 expression, which subsequently enables proinflammatory processes, MMP activation and VSMCs apoptosis. Our study provides evidence that LH1 is a potential critical therapeutic target for AAA.
Theranostics 2021
Background: We used a targeted metabolomics approach to identify fatty acid (FA) metabolites that distinguished patients with coronary artery ectasia (CAE) from healthy Controls and patients with coronary artery disease (CAD). Materials and methods: Two hundred fifty-two human subjects were enrolled in our study, such as patients with CAE, patients with CAD, and Controls. All the subjects were diagnosed by coronary angiography. Plasma metabolomic profiles of FAs were determined by an ultra-high-performance liquid chromatography coupled to triple quadrupole mass spectrometric (UPLC-QqQ-MS/MS). Results: Ninety-nine plasma metabolites were profiled in the discovery sets (n = 72), such as 35 metabolites of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), 10 FAs, and 54 phospholipids. Among these metabolites, 36 metabolites of AA, EPA, and DHA showed the largest difference between CAE and Controls or CAD. 12-hydroxyeicosatetraenoic acid (12-HETE), 17(S)-hydroxydocosahexaenoic acid (17-HDoHE), EPA, AA, and 5-HETE were defined as a biomarker panel in peripheral blood to distinguish CAE from CAD and Controls in a discovery set (n = 72) and a validation set (n = 180). This biomarker panel had a better diagnostic performance than metabolite alone in differentiating CAE from Controls and CAD. The areas under the ROC curve of the biomarker panel were 0.991 and 0.836 for CAE versus Controls and 1.00 and 0.904 for CAE versus CAD in the discovery and validation sets, respectively. Conclusions: Our findings revealed that the metabolic profiles of FAs in the plasma from patients with CAE can be distinguished from those of Controls and CAD. Differences in FAs metabolites may help to interpret pathological mechanisms of CAE.
Frontiers in physiology 2021
Intracerebral hemorrhage (ICH) is a catastrophic stroke with high mortality, and the mechanism underlying ICH is largely unknown. Previous studies have shown that high serum uric acid (SUA) levels are an independent risk factor for hypertension, cardiovascular disease (CVD), and ischemic stroke. However, our metabolomics data showed that SUA levels were lower in recurrent intracerebral hemorrhage (R-ICH) patients than in ICH patients, indicating that lower SUA might contribute to ICH. In this study, we confirmed the association between low SUA levels and the risk for recurrence of ICH and for cardiac-cerebral vascular mortality in hypertensive patients. To determine the mechanism by which low SUA effects ICH pathogenesis, we developed the first low SUA mouse model and conducted transcriptome profiling of the cerebrovasculature of ICH mice. When combining these assessments with pathological morphology, we found that low SUA levels led to ICH in mice with angiotensin II (Ang II)-induced hypertension and aggravated the pathological progression of ICH. In vitro, our results showed that p-Erk1/2-MMP axis were involved in the low UA-induce degradation of elastin, and that physiological concentrations of UA and p-Erk1/2-specific inhibitor exerted a protective role. This is the first report describing to the disruption of the smooth muscle cell (SMC)-elastin contractile units in ICH. Most importantly, we revealed that the upregulation of the p-Erk1/2-MMP axis, which promotes the degradation of elastin, plays a vital role in mediating low SUA levels to exacerbate cerebrovascular rupture during the ICH process.
Translational stroke research 2020
The study aimed to investigate the relationship between mtDNA copy number and the risk of all-cause mortality in stroke. One thousand four hundred eighty-four stroke patients were documented including 273 deaths (127 thrombosis, 52 lacunar, 94 hemorrhage). Patients in the third quartile had the lowest mortality rates in overall stroke and the three subtypes. The lowest quartile of mtDNA copy number (Q1 < 85.85) indicated an increased risk of all-cause mortality in stroke patients (adjusted HR, 1.52; 95% CI, 1.08-2.14; p = 0.017). In the subtype analysis, the risk of all-cause mortality appeared only in lacunar infarct, and the patients in the Q1 (< 87.76) and Q4 (> 150.61) mtDNA copy number groups showed significantly higher risks of HRs (Q1, adjusted HR, 3.87, 95% CI, 1.52-9.83; Q4, adjusted HR, 3.08, 95% CI, 1.16-8.18). Stroke patients with lacunar infarct in mtDNA copy number < 87.76 or > 150.61 were at a high risk of poor outcomes in all-cause mortality.
Journal of cardiovascular translational research 2020
Plasma metabolic profiles were compared between patients with hypertension with and without left ventricular hypertrophy and significantly decreased oleic acid (OA) levels were observed in the peripheral blood of patients with hypertension with left ventricular hypertrophy. We sought to determine the effect and underlying mechanisms of OA on cardiac remodeling. In vitro studies with isolated neonatal mouse cardiomyocytes and cardiac fibroblasts revealed that OA significantly attenuated Ang II (angiotensin II)-induced cardiomyocyte growth and cardiac fibroblast collagen expression. In vivo, cardiac function, hypertrophic growth of cardiomyocytes, and fibrosis were analyzed after an Ang II (1000 ng/kg/minute) pump was implanted for 14 days. We found that OA could significantly prevent Ang II-induced cardiac remodeling in mice. RNA sequencing served as a gene expression roadmap highlighting gene expression changes in the hearts of Ang II-induced mice and OA-treated mice. The results revealed that FGF23 (fibroblast growth factor 23) expression was significantly upregulated in mouse hearts in response to Ang II infusion, which was significantly suppressed in the hearts of OA-treated mice. Furthermore, overexpression of FGF23 in the heart by injection of an AAV-9 vector aggravated Ang II-induced cardiac remodeling and impaired the protective effect of OA on cardiac remodeling. Further study found that OA could suppress Ang II-induced FGF23 expression by inhibiting the translocation of Nurr1 (nuclear receptor-related 1 protein) from the cytoplasm to the nucleus. Our findings suggest a novel role of OA in preventing Ang II-induced cardiac remodeling via suppression of FGF23 expression.
Hypertension (Dallas, Tex. : 1979) 2020
Hypertensive intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease with no effective treatment. Lysyl hydroxylase 3 (LH3) is essential for collagen IV intermolecular crosslinking and stabilization. Deficiency in LH3 affects the assembly and secretion of collagen IV and basement membrane (BM) integrity of vessels. Here, we investigated whether LH3 has significant implications for disease progression and therapeutic intervention. Spontaneous hypertensive ICH of mice was induced by angiotensin II and L-NAME treatment. The adeno-associated virus was delivered into brain by stereotactic injection to knockdown or overexpress LH3. We found LH3 levels were reduced in human patients with ICH and gradually decreased in mice before ICH. LH3 knockdown increased the incidence of hypertensive ICH in mice. The incidence, number, and size of ICHs in mice were markedly reduced by LH3 overexpression. RNA-seq revealed that LH3 overexpression significantly reversed the profound alterations in gene transcriptional profiles of cerebral vessels. LH3 overexpression was sufficient to enhance BM integrity, inhibit matrix metalloproteinase activity, attenuate microglial activation and leukocyte infiltration, and reduce VSMC apoptosis before ICH. These results indicate that LH3 overexpression attenuates susceptibility to hypertensive ICH. We emphasize that LH3 modulation may serve as a viable approach for future investigations of ICH prevention.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2019
Activation of transforming growth factor-β1 (TGF-β1)-Smad3 pathway aggravates myocardial ischemia/reperfusion injury (IRI). We previously showed that glutamine (Gln) protects cardiomyocytes from hypoxia/reoxygenation (H/R) injury under high glucose (HG) conditions. The aim of this study was to investigate whether Gln exerts its protective effect in H/R via inhibiting TGF-β1-Smad3 pathway. In vitro, H9c2 rat cardiomyocytes were treated with Gln with HG (33 mM) and/or H/R. We also performed in vivo experiments in which we treated normal and diabetic rats with Gln or solvent control following IRI. We assessed protein levels of TGF-β1, total Smad3, phosphorylated (p)-Smad3 and cleaved caspase-3 in H9c2 cells and rat myocardium by Western blotting. H9c2 cells treated with HG + H/R exhibited high apoptosis rates, as well as a highly activated TGF-β1-Smad3 pathway. TGF-β1 receptor inhibitor (SB431542) or Smad3 inhibitor (SIS3) reduced HG + H/R induced apoptosis. Similarly, Gln supplementation alleviated apoptosis and decreased p-Smad3 levels. However, Gln's protective effect was significantly weakened by TGF-β1. Diabetic rats treated with Gln had improved hemodynamics, smaller infarct size after IRI, and a significant decrease in TGF-β1-Smad3 pathway activation. We conclude that Gln inhibits HG + H/R induced activation of the TGF-β1-Smad3 pathway and decreases cell apoptosis in cardiomyocytes.
Archives of biochemistry and biophysics 2016
