Fat-1 transgenic mice rich in endogenous omega-3 fatty acids are protected from lipopolysaccharide-induced cardiac dysfunction.

AIMS: Cardiac malfunctions developing in result of sepsis are hard to treat so they eventually contribute to the increased mortality. Previous reports indicated for therapeutic potential of exogenous ω-3 polyunsaturated fatty acids (PUFA) in sepsis, but potential benefits of this compound on the malfunctional heart have not been explored yet. In the present study, we investigated whether the constantly elevated levels of endogenous ω-3 PUFA in transgenic fat-1 mice would alleviate the lipopolysaccharide (LPS)-induced cardiac failure and death. METHODS AND RESULTS: After both wild type (WT) and transgenic fat-1 mice were challenged with LPS, a Kaplan-Meier curve and echocardiography were performed to evaluate the survival rates and cardiac function. Proteomics analysis, RT-PCR, western blotting, immune-histochemistry, and transmission electron microscopy were further performed to investigate the underlying mechanisms. Results showed that transgenic fat-1 mice exhibited the significantly lower mortality after LPS challenge as compared with their WT counterparts (30% vs. 42.5%, P < 0.05). LPS injection consistently impaired the left ventricular contractile function and caused the cardiac injury in the wild type mice, but not significantly affected the fat-1 mice (P < 0.05). Proteomic analyses, ELISA, and immunohistochemistry further revealed that myocardium of the LPS-challenged fat-1 mice demonstrated the significantly lower levels of pro-inflammatory markers and ROS than WT mice. Meaningfully, the LPS-treated fat-1 mice also demonstrated a significantly higher levels of LC3 II/I and Atg7 expressions than the LPS-treated WT mice (P < 0.05), as well as displayed a selectively increased levels of peroxisome proliferator-activated receptor (PPAR) γ and sirtuin (Sirt)-1 expression, associated with a parallel decrease in NFκB activation. CONCLUSIONS: The fat-1 mice were protected from the detrimental LPS-induced inflammation and oxidative stress, and exhibited enhancement of the autophagic flux activities, associating with the increased Sirt-1 and PPARγ signals.

Beneficial Effects of Baduanjin Exercise on Left Ventricular Remodelling in Patients after Acute Myocardial Infarction: an Exploratory Clinical Trial and Proteomic Analysis.

BACKGROUND: The beneficial effects of physical exercise on cardiac remodelling improvement after myocardial infarction have already been suggested. However, the results of previous clinical trials have not been consistent. Moreover, the putative molecular mechanisms leading to the clinically observed effects of physical exercise still remain elusive. AIM: We aimed to evaluate whether the well-defined and strictly controlled traditional Chinese Qigong Baduanjin exercise (BE) would attenuate the adverse left ventricular (LV) remodelling in patients with ST-elevation myocardial infarction (STEMI). METHODS: A total of 110 clinically stable STEMI patients, following successful revascularization of their infarcted coronary arteries, were randomized and enrolled in two groups: 56 were subjected to a 12-week BE-based cardiac rehabilitation programme (BE group), and the remaining 54 were exposed to the usual physical exercise (control group) for the same time period. The primary outcome was the change from baseline to 6 months in the echocardiographic LV end-diastolic volume index (ΔLVEDVi). Proteomic analysis was also performed to uncover associated mechanisms. RESULTS: Compared with the control group, the BE group showed significantly lower ΔLVEDVi (-5.1 ± 1.1 vs. 0.3 ± 1.2 mL/m2, P < 0.01). Proteomic analysis revealed BE-induced variations in the expression of 80 proteins linked to regulation the of metabolic process, immune process, and extracellular matrix reorganization. Furthermore, correlation analyses between the validated serum proteomes and primary endpoint demonstrated a positive association between ΔLVEDVi and MMP-9 expression, but a negative correlation between ΔLVEDVi and CXCL1 expression. CONCLUSION: This is the first study indicating that BE in STEMI patients can alleviate adverse LV remodelling associated with beneficial energy metabolism adaptation, inflammation curbing, and extracellular matrix organization adjustment.

Addition of Chinese herbal remedy, Tongguan Capsules, to the standard treatment in patients with myocardial infarction improve the ventricular reperfusion and remodeling: Proteomic analysis of possible signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongguan Capsules (TGC), a patented Chinese herbal remedy containing Salvia miltiorrhiza, Astragalus membranaceus, Borneolum syntheticum and Grasshopper, has been previously tested in the experimental model of animal hearts subjected to ischemia/reperfusion injury and its cardioprotective effect has been described. AIM OF THE STUDY: This clinical trial was aimed at investigation whether the administration of TGC to patients suffered myocardial infarction (MI), would diminish dilation of the left ventricular (LV) and reduce development of the adverse clinical consequences. METHODS: Eligible patients were enrolled and randomized 1:1 to TGC (4.5 g/d for 6 months) superimposed on standard treatment for MI, or the control group receiving the standard protocol alone. The outcomes of this trial were valued after 6 months and reported as a mean change from the baseline in LV end-systolic volume index (LVESVI) and as a frequency of MI recurrence, target-vessel revascularization, severity of heart failure or significant arrhythmia that required the additional therapy within 6 months. In addition, arrays with a panel of specific antibodies were used to assess levels of major cytokines and other pathophysiologic markers, that prompted conclusions about the mechanisms of the ultimate clinical outcomes in both patient's subgroups. RESULTS: Meaningfully, obtained results indicated that MI patients randomly assigned to the TGC treatment, demonstrated a significant reduction of LVESVI (-4.03 ± 0.73 vs. 1.59 ± 0.43 mL/m2, P < 0.001) and a lower incidence of the major adverse cardiovascular events (5.45% vs. 11.44%, P = 0.033). Meaningfully, those patients consistently demonstrated lower serum levels of major inflammatory cytokines, as well as reduced levels of markers of myocardial apoptosis and fibrosis. CONCLUSION: Addition of TGC to the current conventional treatment of MI patients, significantly reduced their adverse LV remodeling and contributed to the more positive clinical outcome. TRIAL REGISTRATION: ChiCTR-IPR-17011618.

Traditional Chinese medicine, Danlou tablets alleviate adverse left ventricular remodeling after myocardial infarction: results of a double-blind, randomized, placebo-controlled, pilot study.

BACKGROUND: Danlou tablets, a patented Chinese Medicine, have been long approved for the treatment of ischemic heart disease in China. While numerous empirical observations suggested Danlou tablets could decrease frequency and duration of angina pectoris attacks, evidence supporting its efficacy on cardiac remodeling remains inadequate. Therefore, this pilot trial was designed to determine whether Danlou tablets would reduce adverse left ventricular (LV) remodeling in patients with myocardial infarction (MI). METHODS AND RESULTS: Eligible patients with acute MI were enrolled and randomly assigned to Danlou tablets or placebo groups, superimposed on standard treatment for MI. Then, in addition to assessment of the clinical outcome, the changes in LV volumes were evaluated by a serial echocardiography. In total, 83 patients (Danlou tablets 42 and placebo 41) completed 90 days of treatment and had complete baseline and outcome data. Standard echocardiographic evaluations revealed significant differences in the change of LV end-diastolic volume index (LVEDVi) between group of patients treated with Danlou tablets and the placebo group (-4.49 ± 7.29 vs. -0.34 ± 9.01 mL/m2, P < 0.001). The reduction in LVEDVi was independent of beta-blocker, ACE inhibitors/ARBs use. Furthermore, treatment with Danlou tablets significantly reduced LV end-systolic volume index (-4.09 ± 5.85 vs. -0.54 ± 5.72 mL/m2, P < 0.001) and improved the LV ejection fraction (4.83 ± 9.23 vs. 0.23 ± 8.15 %, P < 0.001), as compared to placebo. Meaningfully, the incidence of the major adverse cardiovascular events was also lower in patients receiving Danlou tablets (P < 0.05). CONCLUSION: Superimposed on the standard pharmacologic treatment, Danlou tablets significantly reversed post-MI adverse LV remodeling, thereby contributed to the overall positive clinical outcome. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT02675322 (February 1, 2016).

Serine carboxypeptidase SCPEP1 and Cathepsin A play complementary roles in regulation of vasoconstriction via inactivation of endothelin-1.

The potent vasoconstrictor peptides, endothelin 1 (ET-1) and angiotensin II control adaptation of blood vessels to fluctuations of blood pressure. Previously we have shown that the circulating level of ET-1 is regulated through its proteolytic cleavage by secreted serine carboxypeptidase, cathepsin A (CathA). However, genetically-modified mouse expressing catalytically inactive CathA S190A mutant retained about 10-15% of the carboxypeptidase activity against ET-1 in its tissues suggesting a presence of parallel/redundant catabolic pathway(s). In the current work we provide direct evidence that the enzyme, which complements CathA action towards ET-1 is a retinoid-inducible lysosomal serine carboxypeptidase 1 (Scpep1), a CathA homolog with previously unknown biological function. We generated a mouse strain devoid of both CathA and Scpep1 activities (DD mice) and found that in response to high-salt diet and systemic injections of ET-1 these animals showed significantly increased blood pressure as compared to wild type mice or those with single deficiencies of CathA or Scpep1. We also found that the reactivity of mesenteric arteries from DD mice towards ET-1 was significantly higher than that for all other groups of mice. The DD mice had a reduced degradation rate of ET-1 in the blood whereas their cultured arterial vascular smooth muscle cells showed increased ET-1-dependent phosphorylation of myosin light chain 2. Together, our results define the biological role of mammalian serine carboxypeptidase Scpep1 and suggest that Scpep1 and CathA together participate in the control of ET-1 regulation of vascular tone and hemodynamics.

Phytoestrogen, tanshinone IIA diminishes collagen deposition and stimulates new elastogenesis in cultures of human cardiac fibroblasts.

It has been previously reported that oral or intra-peritoneal administration of tanshinone IIA can alleviate the ventricular hypertrophy and fibrosis that develops in rats after experimental cardiac infarction. Our present studies, performed on cultures of human cardiac fibroblasts, investigated the mechanism by which tanshinone IIA produces these beneficial effects. We found that treatment of cardiac fibroblasts with 0.1-10µM tanshinone IIA significantly inhibited their deposition of collagen I, while enhancing production of new elastic fibers. Moreover, both anti-collagenogenic and pro-elastogenic effects of tanshinone IIA occurred only after selective activation of the G protein-coupled estrogen receptor (GPER). This subsequently leads to initiation of the PKA/CREB phosphorylation pathway that inversely modulated transcription of collagen I and elastin genes. Interestingly, treatment of human cardiac fibroblasts with tanshinone IIA additionally up-regulated the production of the 67-kDa elastin binding protein, which facilitates tropoelastin secretion, and increased synthesis of lysyl oxidase, catalyzing cross-linkings of tropoelastin. Moreover, tanshinone IIA also caused up-regulation in the synthesis of collagenolytic MMP-1, but down-regulated levels of elastolytic MMP-2 and MMP-9. In summary, our data validate a novel mechanism in which tanshinone IIA, interacting with a non-classic estrogen receptor, maintains the proper balance between the net deposition of collagen and elastin, allowing for optimal durability and resiliency of the newly deposited matrix.