β-AR Blockers Suppresses ER Stress in Cardiac Hypertrophy and Heart Failure

Long-term β-adrenergic receptor (β-AR) blockade reduces mortality in patients with heart failure. Chronic sympathetic hyperactivity in heart failure causes sustained β-AR activation, and this can deplete Ca(2+) in endoplasmic reticulum (ER) leading to ER stress and subsequent apoptosis. We tested the effect of β-AR blockers on ER stress pathway in experimental model of heart failure.ER chaperones were markedly increased in failing hearts of patients with end-stage heart failure. In Sprague-Dawley rats, cardiac hypertrophy and heart failure was induced by abdominal aortic constriction or isoproterenol subcutaneous injection. Oral β-AR blockers treatment was performed in therapy groups. Cardiac remodeling and left ventricular function were analyzed in rats failing hearts. After 4 or 8 weeks of banding, rats developed cardiac hypertrophy and failure. Cardiac expression of ER chaperones was significantly increased. Similar to the findings above, sustained isoproterenol infusion for 2 weeks induced cardiac hypertrophy and failure with increased ER chaperones and apoptosis in hearts. β-AR blockers treatment markedly attenuated these pathological changes and reduced ER stress and apoptosis in failing hearts. On the other hand, β-AR agonist isoproterenol induced ER stress and apoptosis in cultured cardiomyocytes. β-AR blockers largely prevented ER stress and protected myocytes against apoptosis. And β-AR blockade significantly suppressed the overactivation of CaMKII in isoproterenol-stimulated cardiomyocytes and failing hearts in rats.Our results demonstrated that ER stress occurred in failing hearts and this could be reversed by β-AR blockade. Alleviation of ER stress may be an important mechanism underlying the therapeutic effect of β-AR blockers on heart failure

Coronavirus Disease 2019 (COVID‐19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin‐Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection

The prevalence of coronavirus disease 2019 (COVID‐19) has posed a great threat to people's health worldwide, bringing a great challenges to the public healthcare systems. A recent study has confirmed that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) uses severe acute respiratory syndrome coronavirus (SARS‐CoV) receptor angiotensin‐converting enzyme 2 (ACE2) for host cell entry.1 ACE2 expression was previously found to correlate with susceptibility to SARS‐CoV infection in vitro.2 As with SARS‐CoV, higher ACE2 expression might also lead to higher risk of SARS‐CoV‐2 infection. See Article by Sommerstein et al. According to available clinical data, ≈15% to 30% of the COVID‐19 patients are with hypertension and ≈2.5% to 15% are with coronary heart disease.3, 4, 5 Angiotensin‐converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) are widely used in the treatment of these cardiovascular diseases. Interestingly, several studies have shown that ACEIs/ARBs exhibit ability to upregulate ACE2 expression in addition to their main pharmacological effect to inhibit angiotensin‐converting enzyme 1 (ACE1) or block angiotensin II type 1 receptor.6, 7, 8 Considering that ACE2 expression might correlate with the susceptibility to SARS‐CoV‐2, intake of ACEIs/ARBs might predispose patients to the infection of SARS‐CoV‐2. Therefore, some cardiologists suggested that patients should discontinue ACEIs/ARBs to avoid the potential increased risk of SARS‐CoV‐2 infection.9 However, there is evidence demonstrating that the activation of the renin‐angiotensin system (RAS) and the downregulation of ACE2 expression are involved in the pathological process of lung injury after SARS‐CoV infection.10 Recently, it has been reported that serum level of angiotensin II is significantly elevated in COVID‐19 patients and exhibits a linear positive correlation to viral load and lung injury.11 Activation of the RAS can cause widespread endothelial dysfunction and varying degrees of multiple organ (heart, kidney, and lung) injuries. Thus, intake of ACEIs/ARBs might probably relieve the lung injury and absolutely decrease heart and renal damage resulting from the RAS activation. These possibilities pose a dilemma for the cardiologists in terms of recommending whether to discontinue ACEIs/ARBs or not. On the basis of the current literature, a viewpoint on the potential influence of ACEIs/ARBs on the onset and severity of SARS‐CoV‐2 infection is proposed in this articl

β-AR blockers suppressed ER stress in hypertrophic and failing hearts of rats.

<p>(A) ER chaperone GRP78 and spliced XBP-1 were increased in AAC rats (1or 4 or 8 weeks after operation), and metoprolol treatment (30 mg/kg/d for 8 weeks) reduced the epression of GRP78 and spliced XBP-1. Proteins were normalized to β-actin. (B) GRP78 was increased in AAC rats (4 weeks), and propranolol treatment (30 mg/kg/d for 4 weeks) reduced the epression of GRP78. Protein was normalized to β-actin. (C) Immunohistochemical analyses of rats’ hearts and number of GRP78, KDEL and CHOP-positive cells per mm². Scale bar, 40 µm. For (A) to (C), *P<0.05 vs. sham, #P<0.05 vs. AAC. (D) GRP78 and spliced XBP-1 was increased in Iso rats, and metoprolol treatment (30 mg/kg/d for 2 weeks) reduced the epression of GRP78 and spliced XBP-1. Proteins were normalized to β-actin. *P<0.05 vs. control, #P<0.05 vs. Iso.</p

Clinical features of severe wasp sting patients with dominantly toxic reaction: analysis of 1091 cases.

BACKGROUND: Massive wasp stings have been greatly underestimated and have not been systematically studied. The aim of this study was to identify the clinical features and treatment strategies of severe wasp stings. METHODS AND FINDINGS: A multicenter retrospective study was undertaken in 35 hospitals and medical centers including 12 tertiary care hospitals and 23 secondary care hospitals in the Hubei Province, China. The detailed clinical data of 1091 hospitalized wasp sting patients were investigated. Over three-fourths (76.9%) of the cases had 10 or more stings and the in-hospital mortality of patients was 5.1%. Forty-eight patients died of organ injury following toxic reactions to the stings, whereas six died from anaphylactic shock. The in-hospital mortality in patients with >10 stings was higher than that of ≤10 stings (5.2% vs. 1.0%, p = 0.02). Acute kidney injury (AKI) was seen in 21.0% patients and most patients required blood purification therapy. Rhabdomyolysis was seen in 24.1% patients, hemolysis in 19.2% patients, liver injury in 30.1% patients, and coagulopathy in 22.5% patients. Regression analysis revealed that high creatinine level, shock, oliguria, and anemia were risk factors for death. Blood purification therapy was beneficial for patients with ≥20 stings and delayed hospital admission of patients (≥4 hours after sting). CONCLUSIONS: In China, most patients with multiple wasp stings presented with toxic reactions and multiple organ dysfunction caused by the venom rather than an anaphylactic reaction. AKI is the prominent clinical manifestation of wasp stings with toxic reaction. High creatinine levels, shock, oliguria, and anemia were risk factors for death

Induction of ER Stress in Human Heart Failure.

<p>ER stress markers including phosphorylated eIF2α (p-eIF2α), phosphorylated PERK (p-PERK), GRP78 and CHOP and apoptosis marker phosphorylated c-Jun (p-c-Jun), were examined in the heart samples from patients with heart failure. (A) ER stress was increased in heart transplant recipients’ failing hearts compared with normal heart. DCM, dilated cardiomyopathy. (B) p1-p9, heart samples of 9 patients undergoing mitral valve replacement; N1 and N2, normal human hearts. Proteins were normalized to β-actin. *<i>P</i><0.05 vs. normal hearts.</p

β-AR blockers suppressed overactivation of Calmodulin Kinase II in rat failing hearts.

<p>(A) Metoprolol alleviated ER stress and overactivation of CaMKII induced by tunicamycin (TM). Cells were pretreated with KN93 (KN, 0.5 µmol/L or 2 µmol/L), metoprolol (M, 10 µmol/L or 20 µmol/L) for 1 hour, and exposed to TM (5 µg/ml) for 24 hours. Cell lysates were then immunoblotted for phosphorylated CaMKII, phosphorylated PERK, GRP78 and CHOP, which were all normalized to β-actin. *P<0.05 vs. control, #P<0.05 vs. TM. (B) Metoprolol suppressed the overactivation of CaMKII in AAC rats. *P<0.05 vs. sham, #P<0.05 vs. AAC.</p

Clinical characteristics of patients with mitral valve replacement.

<p>MI, mitral insufficiency; MS, mitral stenosis; AF, atrial fibrillation; TI, tricuspid insufficiency; MVP, mitral valve prolapse; N/A, not applicable.</p

β-AR blockers suppressed ER stress-mediated apoptosis in cardiac hypertrophy and failure.

<p>(A) and (B) CHOP was increased in AAC rats (4 or 8 weeks after operation), and metoprolol (30 mg/kg/d for 4 or 8 weeks)or propranolol (30 mg/kg/d for 4 or 8 weeks) treatment reduced expression of CHOP. CHOP was normalized to β-actin. (C) Representative images of TUNEL showing cardiac myocytes apoptosis and quantitative analysis of TUNEL-positive myocardial cells in rats. Nuclei of normal cells are blue, and nuclei of apoptosis cells (TUNEL-positive cells) are brown.</p

Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene

Background. Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. Methods and Results. Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n=6, respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. Conclusion. Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF

Hemodynamic parameters in Iso rats and Iso rats with β-AR blocker treatment.

<p>HR, heart rate; PES, end-systolic pressure; PED, end-diastolic pressure; dP/dtmax, maximal slope of systolic pressure increment; dP/dt min maximal slope of diastolic pressure decrement; Iso, isoproterenol; meto, metoprolol. Data are mean ± s.d. *P<0.05 vs. control.</p