RESUMO
The therapeutic effect of sacubitril/valsartan (S/V) on heart failure has been confirmed, while its role in atherosclerosis remains largely unexplored. The present study aimed to investigate the effects of S/V on the expression of metastasisassociated lung adenocarcinoma transcript 1 (MALAT1), inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs) induced by oxidized lowdensity lipoprotein (oxLDL) and to elucidate its possible mechanism. Cell Counting Kit8 assay was used to detect cell viability. Reverse transcriptionquantitative PCR was performed to detect the MALAT1 expression. ELISA was performed to detect the levels of IL1ß, IL6 and TNFα. Flow cytometry was conducted to detect the apoptotic rate of cells. A nitric oxide (NO) detection kit was used to determine the concentration of NO. Western blotting analysis was performed to determine the levels of intercellular cell adhesion molecule (ICAM)1, vascular cell adhesion molecule (VCAM)1, endothelin1, caspase3, Bax, Bcl2, Tolllike receptor 4 (TLR4), p65 and pp65. Compared with the oxLDL group, S/V treatment significantly increased the cell viability, NO concentration and Bcl2 expression, decreased the levels of IL1ß, IL6 and TNFα and reduced the expressions of MALAT1, ICAM1, VCAM1, cleavedcaspase3, Bax, TLR4 and pp65. Overall, the findings suggested that S/V could downregulate the expression of MALAT1, inhibit inflammation and apoptosis and improve endothelial function in oxLDLinduced HUVECs via inactivating the TLR4/NFκB signaling pathway. Therefore, S/V might be utilized as a promising therapeutic strategy for the prevention and treatment of atherosclerosis.
Assuntos
Aminobutiratos/farmacologia , Anti-Inflamatórios/farmacologia , Apoptose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , RNA Longo não Codificante/genética , Tetrazóis/farmacologia , Valsartana/farmacologia , Compostos de Bifenilo , Combinação de Medicamentos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipoproteínas LDL/farmacologia , NF-kappa B/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismoRESUMO
OBJECTIVE: To investigate the stratification risk of catecholamines-beta-adrenoceptor (beta-AR)-cAMP pathway for cardiogenic death events in patients with congestive heart failure (CHF). METHODS: A total of 83 identified CHF patients with a baseline and follow-up plasma levels of norepinephrine (NE) and epinephrine (E), lymphocytes beta-AR density (Bmax), and intralymphocyte cAMP content in peripheral blood were followed up. Major cardiogenic death events were registered. RESULTS: The period between the initial entry and the last follow-up measurement were 51 +/- 16 months, the total duration of clinical follow-up after the last measurement were 14 +/- 8 months. During follow-up, 39 patients died of cardiogenic (sudden death 17 patients, worsening heart failure 22 patients). Persistence of high NE, E, and cAMP from baseline to follow-up were confirmed as risk predicting factors of cardiovascular events. Persistence NE above 4.0 nmol/L, E above 3.5 nmol/L, and the intralymphocyte cAMP content above 3.5 pmd x mg(-1) x pro(-1) from baseline to follow-up were significant adverse prognostic predictors. The major cardiogenic death events rates per 100 patients-years were 1.33 and 4.82 in patients with NE below and above 4.0 nmol/L (HR: 2.91; 95% CI: 1.08-7.33; P = 0.015); were 1.42 and 4.36 in the patients with E levels below and above 3.5 nmol/L (HR: 2.64; 95% CI: 1.02-6.41; P = 0.019); were 1.81 and 4.67 in the patients with the intralymphocyte cAMP content below and above 3.5 pmd x mg(-1) x pro(-1) (HR: 2.79; 95% CI: 1.04-6.83; P = 0.017), but difference was not significant between the beta-AR density below and above median. CONCLUSIONS: Persistent increase in circulating catecholamines and intralymphocyte cAMP content may increase the long-term mortality in CHF patients.
Assuntos
Catecolaminas/sangue , AMP Cíclico/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Receptores Adrenérgicos beta/sangue , Idoso , Morte Súbita Cardíaca , Epinefrina/sangue , Feminino , Humanos , Linfócitos/química , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangueRESUMO
OBJECTIVE: To investigate the association between catecholamine-beta-adrenoceptor (beta-AR)-adenosine 3', 5'-monophosphate (cAMP) system and long-term prognosis in patients with chronic heart failure (CHF). METHODS: The study population comprised 73 patients with CHF (EF: 23% +/- 10%) with a mean follow-up of 3.8 +/- 1.9 years. Plasma levels of norepinephrine (NE) were measured using high performance lipid chromatography, beta-adrenergic receptor density (Bmax) and the content of cAMP in peripheral lymphocytes were calculated using 3H-dihydroalpneolo as ligand and competitive immunoassay, respectively. Deaths due to cardiovascular events within the follow-up period were registered. RESULTS: The total mortality was 64.7%, 57.4% of which was for cardiogenic (worsening heart failure: 32.4%; sudden death: 25.0%). In the cardiogenic death group, plasma levels of NE and epinephrine (E) (3.74 nmol/L +/- 0.09 nmol/L and 3.17 nmol/L +/- 1.0 nmol/L) and the contents of peripheral lymphocyte cAMP (3.64 pmol/mg protein +/- 1.4 pmol/mg protein) were significantly increased as compared with the survival group (2.68 nmol/L +/- 0.07 nmol/L, 2.41 nmol/L +/- 0.24 nmol/L and 2.73 pmol/mg protein +/- 0.9 pmol/mg protein, respectively, all P < 0.01). In the sudden death group, plasma levels of NE and E (5.01 nmol/L +/- 0.06 nmol/L and 4.13 nmol/L +/- 0.08 nmol/L) were significantly increased as compared with the worsening heart failure group (2.49 nmol/L +/- 0.07 nmol/L and 2.33 nmol/L +/- 0.8 nmol/L, all P < 0.001) and to the survival group (2.68 nmol/L +/- 0.07 nmol/L and 2.41 nmol/L +/- 0.14 nmol/L, all P < 0.01). The incidences of sudden death were 0%, 75%, and 100% (chi(2) = 16.018, P < 0.01) in patients with plasma NE < 2.5 nmol/L, NE 2.5 nmol/L - 4.5 nmol/L, and NE > 4.5 nmol/L, respectively. In the worsening heart failure group, the content of peripheral lymphocyte cAMP (4.46 pmol/mg protein +/- 0.18 pmol/mg protein) was significantly increased compared with the sudden death group (2.39 pmol/mg protein +/- 0.9 pmol/mg protein, P < 0.001) and to the survival group (2.73 pmol/mg protein +/- 1.1 pmol/mg protein, P < 0.001). The worsening heart failure death occurences were 5.0%, 72.2%, and 100% (chi(2) = 14.26, P < 0.01) in patients with a content of peripheral lymphocyte cAMP < 2.5 nmol/L, cAMP 2.5 nmol/L - 4.5 nmol/L, and cAMP > 4.5 nmol/L, respectively. Bmax in peripheral lymphocyte was not significantly different (P > 0.05) among the sudden death, worsening heart failure, and survival groups in CHF patients. CONCLUSIONS: Plasma levels of catecholamine increase significantly, and Bmax and the contents of cAMP in peripheral lymphocytes decrease significantly in patients with CHF. High plasma catecholamine levels may be associated with sudden death, and high intralymphocyte cAMP content may be associated with worsening heart failure in CHF patients.