Aim: Matrine is an alkaloid from Sophora alopecuroides L, which has shown a variety of pharmacological activities and potential therapeutic value in cardiovascular diseases. In this study we examined the protective effects of matrine against diabetic cardiomyopathy (DCM) in rats. Methods: Male SD rats were injected with streptozotocin (STZ) to induce DCM. One group of DCM rats was pretreated with matrine (200 mg·kg -1 ·d -1, po) for 10 consecutive days before STZ injection. Left ventricular function was evaluated using invasive hemodynamic examination, and myocardiac apoptosis was assessed. Primary rat myocytes were used for in vitro experiments. Intracellular ROS generation, MDA content and GPx activity were determined. Real-time PCR and Western blotting were performed to detect the expression of relevant mRNAs and proteins. Results: DCM rats exhibited abnormally elevated non-fasting blood glucose levels at 4 weeks after STZ injection, and LV function impairment at 16 weeks. The cardiac tissues of DCM rats showed markedly increased apoptosis, excessive ROS production, and activation of TLR-4/MyD-88/caspase-8/caspase-3 signaling. Pretreatment with matrine significantly decreased non-fasting blood glucose levels and improved LV function in DCM rats, which were associated with reducing apoptosis and ROS production, and suppressing TLR-4/MyD-88/caspase-8/caspase-3 signaling in cardiac tissues. Incubation in a high-glucose medium induced oxidative stress and activation of TLR-4/MyD-88 signaling in cultured myocytes in vitro, which were significantly attenuated by pretreatment with N-acetylcysteine. Conclusion: Excessive ROS production in DCM activates the TLR-4/MyD-88 signaling, resulting in cardiomyocyte apoptosis, whereas pretreatment with matrine improves cardiac function via suppressing ROS/TLR-4 signaling pathway.

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AimIL-1β was considered as an important inflammatory cytokine in diabetic cardiovascular complications. DCM is one of the major manifestations of diabetic cardiovascular complications whose specific mechanisms are still unclear. In this study, we investigated the role of IL-1β in myocytes apoptosis in DCM.MethodsIn the in vitro study, high- glucose medium and/or IL-1β were used to incubate the isolated primary myocytes. siRNA was used to knockdown the irak2 gene expression. Apoptosis was evaluated by Hoechst and TUNEL staining. In the in vivo study, DCM in rats was induced by STZ injection and confirmed by cardiac hemodynamic determinations. The IL-1 receptor antagonist, IL-1Ra was also used to treat DCM rats. Myocardial apoptosis was assessed by TUNEL assay. In both in vitro and in vivo studies, expression levels of GRP-78, IRAK-2 and CHOP were analyzed by Western Blotting. ELISA was employed to exam the IL-1β content in serum and cell supernatants.ResultsMyocytes were not identified as the source of IL-1β secretion under high- glucose incubation. High glucose incubation and/or IL-1β incubation elevated ER- stress mediated myocytes apoptosis which was attenuated by irak2 silencing. Dramatically increased circulating and myocardial IL-1β levels were found in DCM rats which stimulated activation of ER stress and lead to elevated myocytes apoptosis. The administration of IL-1Ra, however, attenuated IRAK2/CHOP induced apoptosis without affecting fasting blood glucose concentration.ConclusionsElevated circulating IL-1β contributed to promote ER stress- induced myocytes apoptosis by affecting IRAK-2/CHOP pathway in DCM.

Hypertensive myocardial remodeling has an important role in the pathophysiology of hypertensive disease. This study suggests that telmisartan (TEL) can inhibit myocardial fibrosis of hypertensive left ventricular hypertrophy (LVH) through the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. Through echocardiography and hemodynamics, it was shown that TEL could improve cardiac function and reduce the degree of hypertensive LVH in hypertensive rats. Through immunoassay, it was shown that TEL could antagonize renin-angiotensin-aldosterone system expression in plasma and myocardial tissue. By Masson staining, Elisa and alkaline hydrolysis assays, it was demonstrated that TEL could significantly inhibit myocardial fibrosis in hypertensive rats and attenuate extracellular matrix-related proteins associated with pressure overload. Western blotting was used to detect the TGF-β1/Smad signaling pathway protein expression of myocardial tissue, and it was further found that TEL could inhibit activation of the TGF-β1/Smad signaling pathway. In conclusion, TEL could inhibit myocardial local angiotensin II (Ang II) level by directly affecting the Ang II receptor. TEL may also restore the balance of matrix metalloproteinases/tissue inhibitor of metalloproteinases, reduce myocardial collagen fibrosis and delay hypertensive LVH by affecting the TGF-β1/Smad signaling pathway.

The period following heart failure hospitalization (HFH) is a vulnerable time with high rates of death or recurrent HFH.OBJECTIVE To evaluate clinical characteristics, outcomes, and treatment response to vericiguat according to prespecified index event subgroups and time from index HFH in the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial. DESIGN, SETTING, AND PARTICIPANTSAnalysis of an international, randomized, placebo-controlled trial. All VICTORIA patients had recent (<6 months) worsening HF (ejection fraction <45%). Index event subgroups were less than 3 months after HFH (n = 3378), 3 to 6 months after HFH (n = 871), and those requiring outpatient intravenous diuretic therapy only for worsening HF (without HFH) in the previous 3 months (n = 801). Data were analyzed between May 2, 2020, and May 9, 2020.INTERVENTION Vericiguat titrated to 10 mg daily vs placebo. MAIN OUTCOMES AND MEASURESThe primary outcome was time to a composite of HFH or cardiovascular death; secondary outcomes were time to HFH, cardiovascular death, a composite of all-cause mortality or HFH, all-cause death, and total HFH. RESULTS Among 5050 patients in the VICTORIA trial, mean age was 67 years, 24% were women, 64% were White, 22% were Asian, and 5% were Black. Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow-up of 10.8 months, the primary event rates were 40.9, 29.6, and 23.4 events per 100 patient-years in the HFH at less than 3 months, HFH 3 to 6 months, and outpatient worsening subgroups, respectively. Compared with the outpatient worsening subgroup, the multivariable-adjusted relative risk of the primary outcome was higher in HFH less than 3 months (adjusted hazard ratio, 1.48; 95% CI, 1.27-1.73), with a time-dependent gradient of risk demonstrating that patients closest to their index HFH had the highest risk. Vericiguat was associated with reduced risk of the primary outcome overall and in all subgroups, without evidence of treatment heterogeneity. Similar results were evident for all-cause death and HFH. Addtionally, a continuous association between time from HFH and vericiguat treatment showed a trend toward greater benefit with longer duration since HFH. Safety events (symptomatic hypotension and syncope) were infrequent in all subgroups, with no difference between treatment arms.CONCLUSIONS AND RELEVANCE Among patients with worsening chronic HF, those in closest proximity to their index HFH had the highest risk of cardiovascular death or HFH, irrespective of age or clinical risk factors. The benefit of vericiguat did not differ significantly across the spectrum of risk in worsening HF.

Cardiac fibrosis is one of the pathological characteristics of diabetic cardiomyopathy (DbCM). Matrine treatment has proven to be effective in cases of organ fibrosis and cardiovascular diseases. In the present study, the anti-fibrosis-associated cardioprotective effects of matrine on DbCM were investigated. Rats with experimental DbCM were administered matrine orally. Cardiac functions were evaluated using invasive hemodynamic examinations. Cardiac compliance was assessed in isolated hearts. Using Sirius Red and fluorescence staining, the collagen in diabetic hearts was visualized. MTT assay was used to select non-cytotoxic concentrations of matrine, which were subsequently used to treat isolated cardiac fibroblasts incubated under various conditions. Western blotting was performed to assess activation of the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. Rats with DbCM exhibited impaired heart compliance and left ventricular (LV) functions. Excessive collagen deposition in cardiac tissue was also observed. Furthermore, TGF-β1/R-Smad (Smad2/3) signaling was revealed to be markedly activated; however, the expression of inhibitory Smad (I-Smad, also termed Smad7) was reduced in DbCM. Matrine administration led to a marked recovery in LV function and heart compliance by exerting inhibitory effects on TGF-β1/R-Smad signaling pathway-induced fibrosis without affecting I-Smad. Incubation with a high concentration of glucose triggered the TGF-β1/R-Smad (Smad2/3) signaling pathway and suppressed I-Smad signaling transduction in cultured cardiac fibroblasts, which led to an increase in the synthesis of collagen. After cardiac fibroblasts had been treated with matrine at non-cytotoxic concentrations without affecting I-Smad, matrine blocked TGF-β1/R-Smad signaling transduction to repress collagen production and deposition. In conclusion, the results of the present study demonstrated that TGF-β1/Smad signaling-associated cardiac fibrosis is involved in the impairment of heart compliance and LV dysfunction in DbCM. By exerting therapeutic effects against cardiac fibrosis via its influence on TGF-β1/Smad signaling, matrine exhibited cardioprotective effects in DbCM.

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