Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias.
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ABSTRACT:
SUBMITTER: Gardner RT
PROVIDER: S-EPMC4315356 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Arrhythmias are a hallmark of myocardial infarction (MI) and increase patient mortality. The cardiac conduction system is implicated in arrhythmias, but how it is altered following MI is poorly understood. We demonstrate complete conduction system restoration during neonatal mouse heart regeneration, versus pathological remodelling at non-regenerative stages. Tissue-cleared whole-organ imaging identified disorganised bundling of conduction fibres after MI, global His/Purkinje disruption and regional loss of connexin-40. Single-cell RNA-sequencing revealed that Purkinje cells undergo specific molecular changes to regenerate the network, versus sustained aberrant electrical alterations during fibrotic repair. This manifested functionally as transition from normal rhythm to pathological conduction delay beyond the regenerative window. Modelling the non-regenerative phenotype in the infarcted human heart implicated these changes as causative for bundle branch block and ventricular dyssynchrony, as observed in patients. These findings elucidate the mechanisms underpinning conduction system regeneration versus repair and reveal the consequences of MI-induced damage for clinical arrhythmogenesis.
2024-10-31 | GSE245872 | GEO
Project description:Cardiac conduction system regeneration prevents arrhythmias after myocardial infarction
| PRJNA1030318 | ENA
Project description:AimOveractivation of the sympathetic nerve may lead to severe ventricular arrhythmias (VAs) after myocardial infarction (MI). Thus, targeting sympathetic nerve activity is an effective strategy to prevent VAs clinically. The superior cervical ganglion (SCG), the extracardiac sympathetic ganglion innervating cardiac muscles, has been found to have a GABAergic signalling system, the physiological significance of which is obscure. We aimed to explore the functional significance of SCG post MI and whether the GABAergic signal system is involved in the process.MethodsAdult male Sprague-Dawley rats were divided into seven different groups. Rats in the MI groups underwent ligation of the left anterior descending coronary artery. All animals were used for electrophysiological testing, renal sympathetic nerve activity (RSNA) testing, and ELISA. Primary SCG sympathetic neurons were used for the in vitro study.ResultsThe GABAA receptor agonist muscimol significantly decreased the ATP-induced increase in intracellular Ca2+ (P < 0.05). GABA treatment in MI rats significantly attenuated the level of serum and cardiac norepinephrine (NE; P < 0.05). Sympathetic activity and inducible VAs were also lower in MI + GABA rats than in MI rats (P < 0.05). Knockdown of the GABAA Rs β2 subunit (GABAA Rβ2 ) in the SCG of MI rats increased the NE levels in serum and cardiac tissue, RSNA and inducible VAs compared with vehicle shRNA (P < 0.05).ConclusionThe GABAergic signalling system is functionally expressed in SCG sympathetic neurons, and activation of this system suppresses sympathetic activity, thereby facilitating cardiac protection and making it a potential target to alleviate VAs.
| S-EPMC6813916 | biostudies-literature
Project description:BackgroundCardiac sympathetic nerve sprouting and the dysregulation of β-adrenergic receptor (β-AR) play a critical role in the deterioration of cardiac function after myocardial infarction (MI). Growing evidence indicates that exercise provides protection against MI. The aims of this study were to investigate whether aerobic exercise following MI could inhibit sympathetic nerve sprouting and restore the balance of β3-AR/β1-AR.MethodsMale Sprague-Dawley rats were divided into three groups: sham-operated control group (SC), MI group (MI), and MI with aerobic exercise group (ME). The rats in ME group were assigned to 8 weeks of exercise protocol (16 m/min, 50 min/d, 5 d/wk). The expression of nerve growth factor (NGF), the sympathetic nerve marker-tyrosine hydroxylase (TH), the nerve sprouting marker-growth associated protein 43 (GAP43), and β1- and β2-AR expression in the peri-infarct area of the left ventricle (LV) were measured by Western blot and immunohistochemistry, while β3-AR expression was determined by Western blot and immunofluorescence. Endothelial nitric oxide synthase (NOS2), phospho-NOS2 (p-NOS2), and neuronal nitric oxide synthase (NOS1) were measured by Western blot.ResultsMI increased LV end-diastolic pressure (LVEDP), and decreased LV systolic pressure (LVSP). Compared with the MI group, aerobic exercise significantly decreased LVEDP and increased LVSP. The protein expression of TH, GAP43 and NGF was significantly increased after MI, which was normalized by exercise. Compared with the SC group, the ratios of β2-AR/β1-AR and β3-AR/β1-AR were elevated in the MI group, and the protein expression of β3-AR and NOS1 increased after MI. Compared with the MI group, the ratios of β2-AR/β1-AR and β3-AR/β1-AR were normalized in the ME group, while the protein expression of β3-AR and NOS1 significantly increased, and NOS2 was activated by exercise.ConclusionsAerobic exercise inhibits cardiac sympathetic nerve sprouting, restores β3-AR/β1-AR balance and increases β3-AR expression through the activation of NOS2 and NOS1 after myocardial infarction.
| S-EPMC4026473 | biostudies-literature
Project description:BackgroundI-123 meta-iodobenzylguanidine (MIBG) imaging has long been employed to noninvasively assess the integrity of human norepinephrine transporter-1 and, hence, myocardial sympathetic innervation. Positron-emitting F-18 meta-fluorobenzylguanidine (MFBG) has recently been developed for potentially superior quantitative characterization. We assessed the feasibility of MFBG imaging of myocardial sympathetic innervation.Methods16 patients were imaged with MFBG PET (30-minute dynamic imaging of chest, followed by 3 whole-body acquisitions between 30 minutes and 4-hour post-injection). Blood kinetics were assessed from multiple samples. Pharmacokinetic modeling with reversible 1- and 2-compartment models was performed. Kinetic rate constants were re-calculated from truncated datasets. All patients underwent concurrent MIBG SPECT.ResultsMFBG myocardial uptake was rapid and sustained; the mean standardized uptake value (SUV (mean ± standard deviation)) was 5.1 ± 2.2 and 3.4 ± 1.9 at 1 hour and 3-4-hour post-injection, respectively. The mean K1 and distribution volume (VT) were 1.1 ± 0.6 mL/min/g and 34 ± 22 mL/cm3, respectively. Both were reproducible when re-calculated from truncated 1-hour datasets (Intraclass Correlation Coefficient of 0.99 and 0.91, respectively). Spearman's ϱ = 0.86 between MFBG SUV and VT and 0.80 between MFBG PET-derived VT and MIBG SPECT-derived heart-to-mediastinum activity concentration ratio.ConclusionMFBG is a promising PET radiotracer for the assessment of myocardial sympathetic innervation.
| S-EPMC10155237 | biostudies-literature
Project description:INTRODUCTION:Parkinson disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA) are characterized by intra-cerebral deposition of the protein alpha-synuclein and are termed synucleinopathies. Lewy body synucleinopathies involve decreased cardiac sympathetic innervation and functional abnormalities in residual noradrenergic terminals. This observational, retrospective, cohort study describes long-term trends in indices of cardiac sympathetic innervation and function in synucleinopathies. METHODS:Patients with PD (N?=?31), PAF (N?=?9), or MSA (N?=?9) underwent repeated 18F-dopamine positron emission tomography (median follow-up 3.5 years). Interventricular septal 18F-dopamine-derived radioactivity 8?min after tracer injection (8' Radioactivity) was used as an index of sympathetic innervation and the slope of mono-exponential decline of radioactivity between 8 and 25?min (k8'-25') as an index of intraneuronal vesicular storage. Healthy volunteers (HVs) (N?=?33) and individuals at high risk of PD (N?=?15) were controls. RESULTS:Upon initial evaluation the groups with PD and orthostatic hypotension (OH), PAF, or PD and no OH had low mean 8' Radioactivity compared to HVs (p?<?0.0001, p?=?0.0002, p?=?0.006) and had elevated k8'-25' (p?=?0.0007, p?=?0.007, p?=?0.06). There was no significant difference between MSA and HVs. In PD 8' Radioactivity decreased by a median of 4% per year and did not decrease in MSA. k8'-25' values did not change during follow-up in any group. CONCLUSIONS:Neuroimaging evidence of decreased vesicular uptake in cardiac sympathetic nerves is present upon initial evaluation of patients with Lewy body synucleinopathies and may provide a biomarker of catecholaminergic dysfunction early in the disease process.
| S-EPMC7031858 | biostudies-literature
Project description:Protein tyrosine phosphatases (PTPs) play essential roles in regulating signaling events in multiple cells by tyrosine dephosphorylation. One of them, PTPσ, appears important in regulating function of plasmacytoid dendritic cells (pDC). Here we report that PTPσ deletion in knockout mice and inhibition with a selective antagonist peptide exacerbated symptoms of experimental autoimmune encephalomyelitis (EAE) by enhancing axon and myelin damage in the spinal cord. PTPσ-/- mice displayed pro-inflammatory profiles in the spinal cord and lymphoid organs following MOG peptide immunization. PTPσ deletion promoted a pro-inflammatory phenotype in conventional DCs and directly regulated differentiation of CD4+ T cells. It also facilitated infiltration of T lymphocytes, activation of macrophages in the CNS and development of EAE. Therefore, PTPσ is a key negative regulator in EAE initiation and progression, which acts by regulating functions of DCs, T cells, and other immune cells. PTPσ may become an important molecular target for treating autoimmune disorders.
| S-EPMC6275552 | biostudies-literature
Project description:The mechanism mediating the development of ventricular arrhythmia (VA) after acute myocardial infarction (AMI) is still uncertain. Thrombin receptor (TR) activation has been proven to be arrhythmogenic in many other situations, and we hypothesize that it may participate in the genesis of post-AMI VA. Using a left coronary artery ligation rat model of AMI, we found that a local injection of hirudin into the left ventricle (LV) significantly reduced the ratio of VA durations to infarction sizing, whereas injection of thrombin receptor-activating peptide (TRAP) increased the ratios of VA duration to infarction sizing. The effects of TR activation on whole-cell currents were investigated in isolated myocytes. TRAP increased a glibenclamide-sensitive outward current. Pretreatment of rats with glibenclamide (4 mg/kg intraperitoneally) eliminated the effects of a local injection of TRAP on the ratios of VA durations to infarction sizing. TR mRNA and protein expression in the ischemic left ventricle had reached its peak by 20 min postligation in the rat AMI model (P < 0.05). TR-immunoreactive myocytes were observed in infarcted LV but were seldom seen in the right ventricle or in the normal heart. By 60 min, TR transcript levels had returned to control levels. We conclude that increased TR activation and expression in the infarcted LV after AMI may contribute to VA through a mechanism involving glibenclamide-sensitive potassium channels.
| S-EPMC2213895 | biostudies-literature
Project description:Danqi soft capsule (DQ) is a traditional Chinese medicine containing Salvia miltiorrhiza and Panax notoginseng; it is safe and efficient in treating ischaemic heart diseases. The purpose of the present study was to assess whether DQ could prevent infarct border zone (IBZ) remodelling and decrease ventricular arrhythmias occurrence in post-myocardial infarction (MI) stage. MI was induced by a ligation of the left anterior descending coronary artery. DQ was administered to the post-MI rats started from 1 week after MI surgery for 4 weeks. The results showed that DQ treatment significantly attenuated tachyarrhythmia induction rates and arrhythmia score in post-MI rats. In echocardiography, DQ improved left ventricular (LV) systolic and diastolic function. Histological assessment revealed that DQ significantly reduced fibrotic areas and myocyte areas, and increased connexin (Cx) 43 positive areas in IBZ. Western blot revealed that DQ treatment significantly reduced the protein expression levels of type I and III collagens, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1) and Smad3 phosphorylation, while increasing Cx43 amounts. Overall, these findings mainly indicated that DQ intervention regulates interstitial fibrosis, Cx43 expression and myocyte hypertrophy by TGF-β1/Smad3 pathway in IBZ, inhibits LV remodelling and reduces vulnerability to tachyarrhythmias after MI. This study presents a proof of concept for novel antiarrhythmic strategies in preventing IBZ remodelling, modifying the healed arrhythmogenic substrate and thus reducing susceptibility to ventricular arrhythmias in the late post-MI period.
| S-EPMC6653321 | biostudies-literature
Project description:Sympathetic activation after myocardial infarction (MI) leads to ventricular arrhythmias (VAs), which can result in sudden cardiac death (SCD). The toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-kB) axis within the hypothalamic paraventricular nucleus (PVN), a cardiac-neural sympathetic nerve centre, plays an important role in causing VAs. An MI rat model and a PVN-TLR4 knockdown model were constructed. The levels of protein were detected by Western blotting and immunofluorescence, and localizations were visualized by multiple immunofluorescence staining. Central and peripheral sympathetic activation was visualized by immunohistochemistry for c-fos protein, renal sympathetic nerve activity (RSNA) measurement, heart rate variability (HRV) analysis and norepinephrine (NE) level detection in serum and myocardial tissue measured by ELISA. The arrhythmia scores were measured by programmed electrical stimulation (PES), and cardiac function was detected by the pressure-volume loop (P-V loop). The levels of TLR4 and MyD88 and the nuclear translocation of NF-kB within the PVN were increased after MI, while sympathetic activation and arrhythmia scores were increased and cardiac function was decreased. However, inhibition of TLR4 significantly reversed these conditions. PVN-mediated sympathetic activation via the TLR4/MyD88/NF-kB axis ultimately leads to the development of VAs after MI.
| S-EPMC9097841 | biostudies-literature