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Angiotensin‐converting enzyme‐2 (ACE2) and Mas receptor are the major components of the ACE2/Ang 1‐7/Mas axis and have been shown to play a protective role in hypertension and hypertensive nephropathy individually. However, the effects of dual deficiency of ACE2 and Mas (ACE2/Mas) on Ang II‐induced hypertensive nephropathy remain unexplored, which was investigated in this study in a mouse model of hypertension induced in either ACE2 knockout (KO) or Mas KO mice and in double ACE2/Mas KO mice by subcutaneously chronic infusion of Ang II. Compared with wild‐type (WT) animals, mice lacking either ACE2 or Mas significantly increased blood pressure over 7‐28 days following a chronic Ang II infusion (P

Transforming growth factor β (TGF-β)/Smad3 signaling plays a central role in chronic heart disease. Here, we report that targeting Smad3 with a Smad3 inhibitor SIS3 in an established mouse model of hypertension significantly improved cardiac dysfunctions by preserving the left ventricle (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS), while reducing the LV mass. In addition, SIS3 treatment also halted the progression of myocardial fibrosis by blocking α-smooth muscle actin-positive (α-SMA+) myofibroblasts and collagen matrix accumulation, and inhibited cardiac inflammation by suppressing interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP1), intercellular cell adhesion molecule-1 (ICAM1) expression, and infiltration of CD3+ T cells and F4/80+ macrophages. Interestingly, treatment with SIS3 did not alter levels of high blood pressure, revealing a blood pressure-independent cardioprotective effect of SIS3. Mechanistically, treatment with SIS3 not only directly inactivated TGF-β/Smad3 signaling but also protected cardiac Smad7 from Smurf2-mediated proteasomal ubiquitin degradation. Because Smad7 functions as an inhibitor for both TGF-β/Smad and nuclear factor κB (NF-κB) signaling, increased cardiac Smad7 could be another mechanism through which SIS3 treatment blocked Smad3-mediated myocardial fibrosis and NF-κB-driven cardiac inflammation. In conclusion, SIS3 is a therapeutic agent for hypertensive heart disease. Results from this study demonstrate that targeting Smad3 signaling with SIS3 may be a novel and effective therapy for chronic heart disease., Graphical Abstract, Meng and colleagues developed a novel and effective therapy for hypertensive heart disease by specifically targeting Smad3, a key mediator of downstream TGF-β signaling, with a Smad3 inhibitor SIS3. They found that SIS3 treatment significantly improved cardiac dysfunctions and suppressed myocardial fibrosis and inflammation in an established mouse model of hypertension.

Purpose: To evaluate myocardial diffuse fibrosis in severe aortic stenosis (SAS) with cardiac magnetic resonance imaging (MRI) T1 mapping technique. Methods: Twenty-seven SAS patients and 15 controls were enrolled and performed cardiac MRI. Left ventricular (LV) structure, function and T1-derived parameters were measured to compare between SAS group and the controls. Correlation between T1-derived parameters and the extent of histologic fibrosis was performed in 15 patients who underwent aortic valve replacement surgery and myocardial biopsy. Results: The SAS group had LV remodeling with ventricular dilatation, hypertrophy, and contractile dysfunction. The native T1 (1336.2±62.5 ms vs. 1277.6±40.7 ms, p = 0.002) and extracellular volume fraction (ECV%) (26.7±2.2% vs. 24.9±2.2%, p = 0.018) were elevated in the SAS in comparison to the controls. Only ECV and λ correlated with the extent of fibrosis as measured by histology. Conclusion: Cardiac MRI with T1 mapping provides a noninvasive approach to evaluate LV myocardial diffuse fibrosis in SAS.

BackgroundThymic stromal lymphopoietin (TSLP) is a mainly epithelial cell-derived cytokine that may be important in initiating T2 allergic inflammation. Anti-TSLP antibody inhibit allergic inflammation. Previous animal studies have evaluated the anti-allergic efficacy of injecting anti-TSLP antibody intraperitoneally, subcutaneously, or intravenously. However, transtracheal instillation, a less invasive route for anti-TSLP antibody administration, is hitherto unstudied. This study evaluates the efficacy of transtracheally instilling anti-TSLP antibody in inhibiting airway inflammation and hyperresponsiveness in OVA-induced asthma model Balb/c mice.MethodsBalb/c mice were randomly divided into four groups: the control group, the OVA-induced asthma model group, the anti-TSLP mAb treatment group (TSLP mAb group), and the IgG2a mAb control group (IgG2a mAb group). Each group contained nine to eleven mice. Mice in the asthma model group were sensitized with OVA to trigger allergic responses and were treated with transtracheal instillation of normal saline. Mice in the TSLP mAb group received transtracheal instillation of anti-TSLP mAb, while mice in the IgG2a group received transtracheal instillation of IgG2a mAb. Both of these groups were then subjected to OVA challenge. Airway responsiveness was measured as an enhanced pause (Penh) using noninvasive plethysmography. The severity of inflammation was evaluated by histopathological examination using the Underwood assessment of the lung sections. Changes in expression of TSLP, TSLP receptor (TSLPR), T-box transcription factor (T-bet), GATA binding protein 3 (GATA3) and forkhead box protein P3 (Foxp3) were assessed using RT-PCR and immunohistochemical staining. ResultsAirway hyperresponsiveness and infiltration of airway inflammatory cells in the TSLP mAb group were significantly reduced, compared with the OVA and the IgG2a mAb groups. Meanwhile，TSLP, GATA3 mRNA expression and GATA3 protein levels were significantly decreased in the TSLP mAb group, compared with the OVA and the IgG2a mAb groups (P＜0.05）. No significant differences were observed in either T-bet or Foxp3 in the lung section of mRNA and protein expression among these four groups (P＞0.05).ConclusionTranstracheal instillation of anti-TSLP antibody attenuated lung inflammation and airway hyperresponsiveness in OVA-induced asthmatic mice, possibly through downregulation of perivascular and peribronchiolar lymphocytes, neutrophils and GATA3 expression in the airway.

Lipoprotein (a) [Lp(a)] is a genetically determined risk factor of coronary artery disease (CAD). Previous genome-wide association studies (GWASs), which were mostly carried out in Caucasians, have identified many Lp(a)-associated SNPs. Here, we performed a GWAS on Lp(a) levels and further explored the relationships between Lp(a)-associated SNPs and CAD severity in 1,403 Han Chinese subjects. We observed that elevated Lp(a) levels were significantly associated with the increased synergy between percutaneous coronary intervention with TAXUS and cardiac surgery (SYNTAX) score and the counts of heavily calcified lesions and long-range lesions (LRLs; P < 0.05), which are defined as lesions spanning >20 mm. Moreover, we identified four independent SNPs, namely, rs7770628, rs73596816, and rs6926458 in LPA, and rs144217738 in SLC22A2, that were significantly associated with Lp(a) levels. We also found that rs7770628 was associated with high SYNTAX scores [odds ratio (OR) (95% CI): 1.37 (1.05–1.80), P = 0.0213, false discovery rate (FDR) = 0.0852], and that rs7770628 and rs73596816 were associated with high risk of harboring LRLs [OR (95% CI): 1.53 (1.17–2.01), P = 0.0018, FDR = 0.0072 and 1.72 (1.19–2.49), P = 0.0040, FDR = 0.0080, respectively]. Our study was a large-scale GWAS to identify Lp(a)-associated variants in the Han Chinese population. Our findings highlight the importance and potential of Lp(a) intervention and expand our understanding of CAD prevention and treatment.