Heart failure is characterized by abnormal β-adrenergic receptor (β-AR) activation and mitochondrial dysfunction. In heart failure, overactivation of β-AR mediates key pathological processes in cardiomyocytes, including oxidative stress, calcium overload and metabolic abnormalities, which subsequently lead to inflammation, myocardial apoptosis and necrosis. Mitochondria are the core organelles for energy metabolism, and also play a vital role in calcium homeostasis, redox balance and signaling transduction. Moderate β-AR activation is conducive to maintaining mitochondrial homeostasis and physiological cardiomyocyte function. However, β-AR overactivation in heart failure disrupts mitochondrial function through multiple mechanisms. Therefore, our review aims to elucidate how β-AR regulates mitochondrial function, particularly under sympathetic stress, impacting oxidative stress, apoptosis, necrosis, and metabolic imbalance. By describing these mechanisms, we seek to propose new insights and therapeutic targets for the prevention and treatment of heart failure.
Heart Failure/physiopathology* ; Humans ; Receptors, Adrenergic, beta/physiology* ; Mitochondria, Heart/physiology* ; Animals ; Oxidative Stress/physiology* ; Myocytes, Cardiac/physiology* ; Apoptosis/physiology* ; Signal Transduction/physiology*

OBJECTIVETo observe the effect of β₃adrenoceptors (β₃-AR) activation on rat thoracic aorta smooth muscle contractility and the possible related mechanism.

METHODSThe endothelium removed thoracic aorta was pre-contracted with 30 mmol/L KCl physiological saline solution (PSS). Then the tension of the thoracic aorta was recorded in presence of BRL37344 (BRL) to determine the action of β₃-AR. The tension of the thoracic aorta was also recorded in the presence of Propranolol (PRA), SR59230A (SR), L-NNA, H-89 and Iberiotoxin (IBTX) respectively to reveal the underling mechanism of β₃-AR activation on rat vascular smooth muscle. Immunohistochemistry was adopted to confirm the existence and the distribution of β₃-AR in rat thoracic aorta.

RESULTSThe results showed that: (1) The thoracic aorta was relaxed by β₃-AR activation, with a relaxation percentage of (10.59 ± 0.79). (2) β₃-AR was expressed in both endothelial and smooth muscle layer in thoracic aorta sections of rats. (3) PRA did not block the effect of BRL on the thoracic aorta. The relaxation actions of BRL could be antagonized by pre-incubating the thoracic aorta with SR. (4) L-NNA (a NOS inhibitor) and H-89 (a PKA inhibitor) reversed the relaxation effect of BRL on vascular smooth muscle. (5) The effect of BRL was decreased after application of Ibriotoxin (IBTX), a large conductance calcium dependent potassium channel blocker.

CONCLUSIONThe results confirmed that activation of β₃-AR led to relaxation of thoracic aorta smooth muscle. The relaxation action of β₃-AR on smooth muscle of rat thoracic aorta was related to activation of NOS and PKA signaling pathway. Large conductance Ca²⁺-K⁺ channels were involved in the relaxation action of β₃-AR activation on rat thoracic aorta smooth muscle.

Animals ; Aorta, Thoracic ; physiology ; In Vitro Techniques ; Isoquinolines ; Large-Conductance Calcium-Activated Potassium Channels ; physiology ; Muscle Contraction ; Muscle Relaxation ; Muscle, Smooth, Vascular ; physiology ; Nitroarginine ; Peptides ; Propanolamines ; Propranolol ; Rats ; Receptors, Adrenergic, beta-3 ; physiology ; Signal Transduction ; Sulfonamides

OBJECTIVETo investigate the role of long non-coding RNA (lncRNA) BC088414 in hypoxic-ischemic injury of neural cells.

METHODSRat adrenal pheochromocytoma (PC12) cells were divided into four groups: normoxic, oxygen glucose deprivation (OGD), siRNA-normoxic (siRNA group) and siRNA-OGD (n=3 each). Cells were incubated in glucose-free and serum-free DMEM medium under the conditions of 37℃ and 1% O2+99% N2/CO2 for 6 hours to establish an in vitro hypoxic-ischemic model. Quantitative real-time PCR was used to measure mRNA expression of lncRNA BC088414, β2-adrenoceptor (Adrb2), and caspase-6 (CASP6). siRNAs were used to inhibit BC088414 expression in PC12 cells. The TUNEL method was used to measure cell apoptosis.

RESULTSThe OGD group had a significantly higher cell apoptotic index than the normoxic group (P<0.01). After inhibition of BC088414 expression, the OGD group had a significantly reduced apoptotic index (P<0.05). The OGD group had significantly higher mRNA expression levels of lncRNA BC088414, Adrb2, and CASP6 compared with the normoxic group (P<0.05). The siRNA -normoxic group had significantly lower mRNA expression levels of Adrb2 and CASP6 than the normoxic group (P<0.05), and the siRNA-OGD group also had significantly lower mRNA expression levels of Adrb2 and CASP6 than the OGD group (P<0.05).

CONCLUSIONSLncRNA BC088414 may promote apoptosis through Adrb2 and CASP6 and aggravate neural cell injury induced by hypoxia-ischemia.

Animals ; Apoptosis ; Caspase 6 ; genetics ; physiology ; Cell Hypoxia ; Neurons ; pathology ; PC12 Cells ; RNA, Long Noncoding ; physiology ; RNA, Messenger ; analysis ; Rats ; Receptors, Adrenergic, beta-2 ; genetics ; physiology

Since the autoantibodies against the second extracellular loop of &beta;(1)-adrenoceptor (&beta;(1)-AABs) have been found in the sera of patients with idiopathic dilated cardiomyopathy (IDCM), the involvement of autoimmune mechanisms in the pathogenesis of many cardiovascular diseases has extensively been investigated. Our previous study found that urinary occult blood and protein excretion were frequently found in the rats with positive &beta;(1)-AABs, but the mechanisms are unclear. Therefore, we infused the &beta;(1)-AABs into the vein periodically in an attempt to investigate whether &beta;(1)-AABs could induce morphological and functional changes in the kidneys of adult and aged rats and explore the possible mechanisms. The synthetic peptide according to the sequences of the second extracellular loop of &beta;(1)-adrenoceptor (&beta;(1)-AR-ECII) was used to immunize the adult rats to acquire enough &beta;(1)-AABs for use. Neonatal rat ventricular myocytes (NRVMs) culture was used to observe the biological effects of &beta;(1)-AABs on the beating rate. The purified &beta;(1)-AABs were transfused into the vein of rats. The sera level of blood urea nitrogen (BUN), creatinine (CR), uric acid (UA), urinary specific gravity, protein excretion, occult blood and urinary glucose were detected at the different time points by biochemistry and urine analyzers. HE and Masson's trichrome staining were used to detect the changes in kidney structure of passively immunized rats. Enhanced green fluorescent protein (EGFP) and &beta;(1)-AR-EGFP plasmids were transfected into the human embryonic kidney 293 (HEK293) cells in order to observe the changes in cell injury with the treatment of &beta;(1)-AABs. It was found that the sera level of BUN, CR and UA increased gradually and the ratio of BUN to CR decreased progressively with the administration of &beta;(1)-AABs. The increasing of proteinuria, urinary occult blood and urinary glucose was detected by urine analyzer in &beta;(1)-AABs group. By HE and Masson's coloration, lots of mononuclear cell infiltration and collagen fibers deposition could be observed at the 24th week of immunization. After the treatment of &beta;(1)-AABs, the caspase-3 activity increased significantly in the HEK293 cells transfected with &beta;(1)-AR-EGFP plasmids, while no significant changes were observed for lactate dehydrogenase (LDH) activity. The results indicate that long-term presence of &beta;(1)-AABs can induce the morphological and functional damage of the kidneys in adult and aged rats.
Acute Kidney Injury ; immunology ; physiopathology ; Animals ; Autoantibodies ; immunology ; HEK293 Cells ; Humans ; Myocytes, Cardiac ; physiology ; Rats ; Receptors, Adrenergic, beta-1 ; immunology

OBJECTIVETo investigate the effects of exhaustive exercise on contraction mediated by beta-adrenoceptor (beta-AR) in rat cardiac myocytes and to analyze the mechanism by which cardiac systolic dysfunction is caused after exhaustive exercise.

METHODSSixteen SD rats were divided randomly into sedentary group and trained group. Cardiac myocytes were isolated from sedentary group and trained group after five times of exhaustive exercise in one week. Shortening response to norepinephrine (NE), time-to-peak contraction (TTP) and time-to-95% relaxation (R95) were measured after alpha1-AR were blocked. Also shortening responses to different levels of NE were observed.

RESULTSShortening amplitudes in trained rat cardiomyocytes were lower than that in sedentary group. Compared with sedentary group, shortening amplitudes induced by beta-AR stimulation were significantly decreased, meanwhile TTPs and R95 were prolonged when beta-AR were activated in trained rat cardiomyocytes. beta-AR responsiveness to NE was weakened in trained group compared with that in sedentary group.

CONCLUSIONDecreased shortening cardiomyocyte systolic function stimulating by beta-AR could result in cardiac systolic dysfunction after exhaustive exercise.

Animals ; Male ; Myocardial Contraction ; Myocytes, Cardiac ; physiology ; Physical Conditioning, Animal ; physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta-1 ; blood

BACKGROUNDChronic obstructive pulmonary disease (COPD) is a heterogeneous and complex disease of which the pathogenesis remains largely unknown. Many factors could influence COPD development and progression. One of them is the genetic risk factor. A severe hereditary deficiency of alpha-1 antitrypsin is the best genetic proof. Four single nucleotide polymorphisms (SNPs) of beta2-adrenergic receptor (&beta;(2)AR) result in single amino acid substitution. Two loci had been extensively studied and found that they could change the function of &beta;(2)AR. Two SNPs consist of substitutions of glycine for arginine at amino acid position 16, glutamic acid for glutamine at position 27. Many studies proved that polymorphisms at position 16 and 27 altered the lung function of COPD patients or the patient's susceptibility to the development of COPD. However, there was no exclusive conclusion. Therefore, a meta analysis was done to investigate the effect of polymorphisms in the &beta;2-adrenergic receptor (ADRB2) gene on the risk of COPD and lung function.

METHODSComprehensive searches of MEDLINE, Embase, Ovid, HighWire, Cochrane Library, and Chinese databases (CBMdisc, VIP, CNKI, and Wanfang data) from January 1980 to September 2011 were performed, using the keywords: COPD OR chronic obstructive pulmonary disease AND adrenoreceptor OR adrenergic receptor AND polymorphism OR mutation OR variation. Case-control research or cross sectional studies in which diagnosis of COPD met the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines; all the studies reported the ADRB2 genotype at position 16 or 27. Outcomes measured were genotype frequency and forced expiratory volume in the first second (FEV(1)%) in both the case and control.

RESULTSTwelve case-control studies and eight cross-sectional studies were included. Compared to the control (n = 1225), neither Gly/Gly (n = 527) nor Arg/Arg (n = 422) homozygotes at position 16 demonstrated increased susceptibility to COPD, with odds ratios (ORs) of 0.95 (95%CI (0.68, 1.31), z = 0.33, P = 0.740) and 0.82 (95%CI (0.52, 1.28), z = 0.88, P = 0.381), respectively. Similar results were obtained for position 27, with ORs of 0.97 (95%CI (0.77, 1.23), z = 0.21, P = 0.833) for Glu/Glu homozygotes (n = 357) and 0.82 (95%CI (0.53, 1.29), z = 0.85, P = 0.393) for Gln/Gln homozygotes (n = 704) (control = 1183). In patients with COPD, Arg/Arg homozygotes (n = 41) had a similar FEV1% compared with Gly/Gly homozygotes (n = 102) (standardized mean difference (SMD) = 0.88, 95%CI (-0.85, 2.62), z = 1.00, P = 0.319). The genotype distribution was different between Caucasian and Asian populations (all P < 0.05 except the genotype Arg/Gly) for both position 16 and 27.

CONCLUSIONSPolymorphisms of ADRB2 at positions 16 and 27 did not change the risk of COPD nor affect lung function or disease severity. The genotype distribution for these polymorphisms was different between Caucasian and Asian populations.

Case-Control Studies ; Cross-Sectional Studies ; Forced Expiratory Volume ; physiology ; Genetic Predisposition to Disease ; genetics ; Humans ; Polymorphism, Genetic ; genetics ; Pulmonary Disease, Chronic Obstructive ; genetics ; physiopathology ; Receptors, Adrenergic, beta-2 ; genetics ; Respiratory Function Tests

BACKGROUND/AIMS: The blunted ventricular systolic and diastolic contractile responses to physical and pharmacological stress in cirrhosis are termed cirrhotic cardiomyopathy (CCM). CCM has been known to involve multiple defects in the beta-adrenergic signaling pathway. The aim of this study was to determine whether cirrhotic patients have blunted cardiac responses to catecholamine stimulation through dobutamine stress echocardiography (DSE). METHODS: Seventy-one cirrhotic patients with normal left ventricular (LV) chamber size and ejection fraction were enrolled. The LV systolic and diastolic functions were evaluated by two-dimensional and Doppler echocardiography at rest and during peak dobutamine infusion (40 microg/kg/min). An abnormal response was defined as a decrease of less than 10% in LV end-diastolic volume, a decrease of less than 20% in end-systolic volume, and an increase of less than 10% in LV ejection fraction (EF) at peak dobutamine infusion, based on previously used criteria. The early/late diastolic flow (E/A) ratio and diastolic parameters were also measured. RESULTS: A blunted LV response to dobutamine was observed in 18 of 71 cirrhotic patients (25.4%). The baseline EF was significantly higher in 18 patients with a blunted DSE response than that of those with a normal DSE response (P<0.05). The baseline and peak E/A ratios, which are common diastolic dysfunction markers, were higher in the cirrhosis group than in the control group (P<0.001). No adverse events associated with DSE were observed. CONCLUSIONS: Blunted cardiac responses to dobutamine stimulation, which are implicated in defects in the beta-adrenergic signaling pathway, might contribute to the pathogenesis of CCM in patients with cirrhosis.
Adrenergic beta-1 Receptor Agonists/*diagnostic use ; Adult ; Aged ; Dobutamine/*diagnostic use ; Echocardiography, Stress ; Female ; Heart Diseases/complications/physiopathology/*ultrasonography ; Humans ; Liver Cirrhosis/*complications/physiopathology ; Male ; Middle Aged ; Receptors, Adrenergic, beta-1/chemistry/metabolism ; Severity of Illness Index ; Ventricular Function, Left/physiology

Evidence suggests that the deterioration of communication between the sympathetic nervous system and cardiovascular system always accompanies the aging of human and animals. Cardiac sympathetic norepinephrine (NE) transporter (NET) on presynaptic membrane is a predominant component to eliminate released NE in the synaptic cleft and maintains the sensitivity of the beta-adrenergic receptor (beta-AR). In the present study, we investigated NET and beta1-AR mRNA levels and sympathetic nerve density in cardiac sympathetic ganglion and left ventricular myocardium in 2- and 16-month-old rats with Northern blot analysis and immunohistochemistry. The expression levels of NET mRNA, NET protein and beta1-AR mRNA in the ganglia or myocardia of 16-month-old rats were markedly reduced by 67%, 26%, and 43%, respectively, in comparison with those in 2-month-old rats. Our results also show that aging induces a strong decrease of the catecholaminergic nerve fiber density.
Aging ; physiology ; Animals ; Gene Expression Regulation ; genetics ; Male ; Myocardium ; metabolism ; Norepinephrine Plasma Membrane Transport Proteins ; genetics ; metabolism ; RNA, Messenger ; genetics ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta-1 ; metabolism

AIMTo provide further evidence for the synthesis of catecholamines (CAs) in lymphocytes and to investigate the effect of the endogenous CAs synthesized by lymphocytes on function of the lymphocytes themselves and the receptor mechanisms involved in the effect.

METHODSRT-PCR was performed to detect the expression of TH mRNA in the lymphocytes from the mesenteric lymph nodes of rats. Different concentrations of pargyline, an inhibitor of monoamine oxydase, and antagonists of alpha1-, alpha2-, beta1-, and beta2-adrenergic receptor (AR) were added to the lymphocyte cultures, and then proliferative response of the lymphocytes to mitogen concanavalin A (Con A) were measured via methyl-thiazole-tetrazolium (MTT) assay.

RESULTSThe lymphocytes could express TH mRNA, and the expression of TH mRNA was significantly higher in the Con A-activated lymphocytes than in the resting ones. The treatment of pargyline of 10(-6) and 10(-5) mol/L (not 10(-7) mol/L) notably attenuated Con A-induced lymphocyte proliferation. Beta2-AR antagonist ICI118551 (10(-7) and 10(-6) mol/L) completely blocked, but alpha1-AR antagonist corynanthine and alpha2-AR antagonist yohimbine (10(-7) and 10(-6) mol/L) partly blocked the suppressive effect of pargyline on the Con A-induced lymphocyte proliferation. Nevertheless, atenolol, an antagonist of beta1-AR, had no blocking effect on pargyline inhibition of lymphocyte proliferation.

CONCLUSIONLymphocytes have the ability to synthesize CAs and the ability is enhanced in the activated lymphocytes. The endogenous CAs synthesized by lymphocytes can inhibit T cell proliferation and the inhibition of T cells by the CAs is mediated predominantly by beta2-AR on the lymphocytes.

Animals ; Catecholamines ; biosynthesis ; physiology ; Cell Proliferation ; drug effects ; Concanavalin A ; pharmacology ; Female ; Lymphocyte Activation ; Lymphocytes ; metabolism ; Male ; Neuroimmunomodulation ; physiology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta ; physiology ; T-Lymphocytes ; cytology ; immunology ; Tyrosine 3-Monooxygenase ; genetics ; metabolism

The aim of the present study is to investigate the role of &beta;(2)-adrenoreceptor (&beta;(2)-AR) in ischemic preconditioning (IP) in isolated rat heart model of ischemia/reperfusion (I/R). Sprague-Dawley rat hearts were quickly removed, mounted on Langendorff apparatus, and perfused with Krebs-Henseleit (KH) solution. After the initial stabilization period, the rats were randomly divided into 6 groups including control group (perfused for an additional 20 min), IP group (4 cycles of 5 min of ischemia followed by 5 min of reflow), isoproterenol (ISO) group (10 nmol/L ISO perfusion for 5 min followed by 5 min washout), IP + ICI118551 group (55 nmol/L ICI118551 perfusion for 5 min before and throughout IP), ISO + ICI118551 group (55 nmol/L ICI118551 perfusion for 5 min before and throughout ISO treatment), ICI118551 group (55 nmol/L ICI118551 perfusion for 20 min). After these treatments, all hearts were followed by 30 min of no-flow ischemia and 30 min of reperfusion. A computer-based electrophysiological recorder system was used to measure changes of the maximal rate of pressure increase in systole phase (+dp/dt(max)), maximal rate of pressure decrease in diastole phase (-dp/dt(max)), and difference of left ventricular pressure (ΔLVP). Then cardiomyocytes from these hearts were isolated by 5 min of Ca(2+)-free buffer perfusion and 25 min of collagenase perfusion. The ventricles were chopped and filtered. The myocytes were resuspended in KB buffer. The contraction and the viability of cardiomyocytes were measured. Lactate dehydrogenase (LDH) concentration in coronary effluent was assayed with assay kit. The results showed that both IP and ISO significantly increased the values of ±dp/dt(max), ΔLVP, the contraction and viability of cardiomyocytes, shortened the time-to-peak contraction (TTP), and decreased the release of LDH in coronary effluent. ICI118551, a selective &beta;(2)-AR antagonist, blocked these effects. Either the time-to-50% relaxation (R(50)) or the time-to-100% relaxation (R(100)) had no significant differences between groups. Our results indicate that the cardioprotection of IP was mediated by &beta;(2)-AR in isolated rat hearts subjected to I/R injury.
Animals ; Heart ; physiology ; In Vitro Techniques ; Ischemic Preconditioning, Myocardial ; L-Lactate Dehydrogenase ; metabolism ; Myocardial Contraction ; Myocardial Reperfusion Injury ; metabolism ; Myocytes, Cardiac ; physiology ; Perfusion ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta-2 ; metabolism ; Reperfusion Injury