Yidong Wang

SIRT3 in cardiovascular diseases: Emerging roles and therapeutic implications

SIRT3 belongs to a highly conserved protein family of histone deacetylases and it is rich in mitochondria. As acetyl-modification is one of the important post-translational modifications that prevail in the mitochondria, it is not surprising that SIRT3 plays a key regulatory role in this organelle. SIRT3 has a wide range of substrates that are involved in the physiological and pathological processes of oxidative stress, ischemia-reperfusion injury, mitochondrial metabolism homeostasis and cellular death. These pathophysiological processes are considered as the underlying mechanisms of diseases like cardiac hypertrophy, myocardial infarction and heart failure, indicating the potential roles of SIRT3 in cardiovascular diseases. In this review, we will summarize the emerging roles and therapeutic implications of SIRT3 in cardiovascular diseases by providing an update on the latest understanding of its functions.

EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling

Rationale: Cardiac fibrosis is a common feature in left ventricular remodeling that leads to heart failure, regardless of the cause. EphrinB2 (erythropoietin-producing hepatoma interactor B2), a pivotal bidirectional signaling molecule ubiquitously expressed in mammals, is crucial in angiogenesis during development and disease progression. Recently, EphrinB2 was reported to protect kidneys from injury-induced fibrogenesis. However, its role in cardiac fibrosis remains to be clarified. Objective: We sought to determine the role of EphrinB2 in cardiac fibrosis and the underlying mechanisms during the pathological remodeling process. Methods and Results: EphrinB2 was highly expressed in the myocardium of patients with advanced heart failure, as well as in mouse models of myocardial infarction and cardiac hypertrophy induced by angiotensin II infusion, which was accompanied by myofibroblast activation and collagen fiber deposition. In contrast, intramyocardial injection of lentiviruses carrying EphrinB2-shRNA ameliorated cardiac fibrosis and improved cardiac function in mouse model of myocardial infarction. Furthermore, in vitro studies in cultured cardiac fibroblasts demonstrated that EphrinB2 promoted the differentiation of cardiac fibroblasts into myofibroblasts in normoxic and hypoxic conditions. Mechanistically, the profibrotic effect of EphrinB2 on cardiac fibroblast was determined via activating the Stat3 (signal transducer and activator of transcription 3) and TGF-&bgr; (transforming growth factor-&bgr;)/Smad3 (mothers against decapentaplegic homolog 3) signaling. We further determined that EphrinB2 modulated the interaction between Stat3 and Smad3 and identified that the MAD homology 2 domain of Smad3 and the coil–coil domain and DNA-binding domain of Stat3 mediated the interaction. Conclusions: This study uncovered a previously unrecognized profibrotic role of EphrinB2 in cardiac fibrosis, which is achieved through the interaction of Stat3 with TGF-&bgr;/Smad3 signaling, implying a promising therapeutic target in fibrotic diseases and heart failure.

Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis

Cathepsin B (CatB) is a cysteine proteolytic enzyme widely expressed in various cells and mainly located in the lysosomes. It contributes to the pathogenesis and development of many diseases. However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC model by intraperitoneal injection of coxsackievirus B3 (CVB3) into mice. At day 7 and day 28, we found CatB was significantly activated in hearts from VMC mice. Compared with the wild-type mice receiving equal amount of CVB3, genetic ablation of CatB (Ctsb-/-) significantly improved survival, reduced inflammatory cell infiltration, decreased serum level of cardiac troponin I, and ameliorated cardiac dysfunction, without altering virus titers in hearts. Conversely, genetic deletion of cystatin C (Cstc-/-), which markedly enhanced CatB levels in hearts, distinctly increased the severity of VMC. Furthermore, compared with the control, we found the inflammasome was activated in the hearts of wild-type mice with VMC, which was attenuated in the hearts of Ctsb-/- mice but was further enhanced in Cstc-/- mice. Consistently, the inflammasome-initiated pyroptosis was reduced in Ctsb-/- mice hearts and further increased in Cstc-/- mice. These results suggest that CatB aggravates CVB3-induced VMC probably through activating the inflammasome and promoting pyroptosis. This finding might provide a novel strategy for VMC treatment.

Heme Oxygenase-1 in Macrophages Drives Septic Cardiac Dysfunction via Suppressing Lysosomal Degradation of Inducible Nitric Oxide Synthase

Rationale: To date, our understanding of the role of HO-1 (heme oxygenase-1) in inflammatory diseases has mostly been limited to its catalytic function and the potential for its heme-related catabolic products to suppress inflammation and oxidative stress. Whether and how HO-1 in macrophages plays a role in the development of septic cardiac dysfunction has never been explored. Objective: Here, we investigated the role of macrophage-derived HO-1 in septic cardiac dysfunction. Methods and Results: Intraperitoneal injection of lipopolysaccharide significantly activated HO-1 expression in cardiac infiltrated macrophages. Surprisingly, we found that myeloid conditional HO-1 deletion in mice evoked resistance to lipopolysaccharide-triggered septic cardiac dysfunction and lethality in vivo, which was accompanied by reduced cardiomyocyte apoptosis in the septic hearts and decreased peroxynitrite production and iNOS (inducible NO synthase) in the cardiac infiltrated macrophages, whereas proinflammatory cytokine production and macrophage infiltration were unaltered. We further demonstrated that HO-1 suppression abolished the lipopolysaccharide-induced iNOS protein rather than mRNA expression in macrophages. Moreover, we confirmed that the inhibition of HO-1 promoted iNOS degradation through a lysosomal rather than proteasomal pathway in macrophages. Suppression of the lysosomal degradation of iNOS by bafilomycin A1 drove septic cardiac dysfunction in myeloid HO-1–deficient mice. Mechanistically, we demonstrated that HO-1 interacted with iNOS at the flavin mononucleotide domain, which further prevented iNOS conjugation with LC3 (light chain 3) and subsequent lysosomal degradation in macrophages. These effects were independent of HO-1’s catabolic products: ferrous ion, carbon monoxide, and bilirubin. Conclusions: Our results indicate that HO-1 in macrophages drives septic cardiac dysfunction. The mechanistic insights provide potential therapeutic targets to treat septic cardiac dysfunction.

Pharmacological Therapy of Abdominal Aortic Aneurysm: An Update

BACKGROUND Abdominal aortic aneurysm (AAA), a progressive segmental abdominal aortic dilation, is associated with high mortality. AAA is characterized by inflammation, smooth muscle cell (SMC) depletion and extracellular matrix (ECM) degradation. Surgical intervention and endovascular therapy are recommended to prevent rupture of large AAAs. Unfortunately, there is no reliable pharmacological agent available to limit AAA expansion. In the past decades, extensive investigations and a body of ongoing clinical trials aimed at defining potent treatments to inhibit and even regress AAA growth. CONCLUSION In this review, we summarized recent progress of potential strategies, particularly macrolides, tetracyclines, statins, angiotensin converting enzyme inhibitors, angiotensin receptor blocker, corticosteroid, anti-platelet drugs and mast cell stabilizers. We also consider recently identified novel molecular targets, which have potential to be translated into clinical practice in the future.

Association of serum ADAMTS7 levels and genetic variant rs1994016 with acute coronary syndrome in a Chinese population: A case control study

BACKGROUND AND AIMS Acute coronary syndrome (ACS) is commonly caused by rupture or erosion of coronary atherosclerotic plaques and secondary thrombus formation. Metalloproteinase ADAMTS7 was found to play an important role in atherogenesis. This study aimed to explore the association of serum ADAMTS7 levels and rs1994016 polymorphism at ADAMTS7 locus with ACS in a Chinese population. METHODS 1881 patients who underwent coronary angiography were consecutively recruited. Among them, 426 patients were matched for case-controlled analysis. Serum ADAMTS7 levels were determined through enzyme-linked immunosorbent assay (ELISA) and rs1994016 polymorphism was detected by polymerase chain reaction (PCR). RESULTS Serum ADAMTS7 levels in patients with unstable angina pectoris were much higher than in non-atherosclerotic patients, however, no difference was found among non-atherosclerotic patients, the coronary atherosclerosis subgroup and stable angina pectoris subgroup. A higher serum ADAMTS7 level was found in the ACS group than in the non-ACS group (0.61 ± 0.04 vs. 0.47 ± 0.02 ng/mL, p = 0.002) and serum ADAMTS7 level was found to be an independent risk factor for ACS after adjusting for major confounding factors (OR:2.81, 95% CI:1.33-5.93, p = 0.007). ADAMTS7 rs1994016 CT/TT polymorphism was negatively associated with the risk of ACS (OR:0.40, 95% CI:0.22-0.71, p = 0.002). Meanwhile, crossover analysis revealed that in CT/TT homozygotes, ACS risk was reduced nearly 80% in patients with serum ADAMTS7 levels <0.594 ng/mL (Interaction p = 0.002). CONCLUSIONS Serum level of ADAMTS7 was positively associated and rs1994016 CT/TT genotype was negatively associated with the risk of ACS. Patients with lower serum ADAMTS7 level and rs1994016 CT/TT genotype are less likely to suffer from ACS in a Chinese population.

Deficiency of CCAAT/enhancer-binding protein homologous protein (CHOP) prevents diet-induced aortic valve calcification in vivo

Aortic valve (AoV) calcification is common in aged populations. Its subsequent aortic stenosis has been linked with increased morbidity, but still has no effective pharmacological intervention. Our previous data show endoplasmic reticulum (ER) stress is involved in AoV calcification. Here, we investigated whether deficiency of ER stress downstream effector CCAAT/enhancer‐binding protein homology protein (CHOP) may prevent development of AoV calcification. AoV calcification was evaluated in Apoe−/− mice (n = 10) or in mice with dual deficiencies of ApoE and CHOP (Apoe−/−CHOP−/−, n = 10) fed with Western diet for 24 weeks. Histological and echocardiographic analysis showed that genetic ablation of CHOP attenuated AoV calcification, pro‐calcification signaling activation, and apoptosis in the leaflets of Apoe−/− mice. In cultured human aortic valvular interstitial cells (VIC), we found oxidized low‐density lipoprotein (oxLDL) promoted apoptosis and osteoblastic differentiation of VIC via CHOP activation. Using conditioned media (CM) from oxLDL‐treated VIC, we further identified that oxLDL triggered osteoblastic differentiation of VIC via paracrine pathway, while depletion of apoptotic bodies (ABs) in CM suppressed the effect. CM from oxLDL‐exposed CHOP‐silenced cells prevented osteoblastic differentiation of VIC, while depletion of ABs did not further enhance this protective effect. Overall, our study indicates that CHOP deficiency protects against Western diet‐induced AoV calcification in Apoe−/− mice. CHOP deficiency prevents oxLDL‐induced VIC osteoblastic differentiation via preventing VIC‐derived ABs releasing.