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Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias.

Gardner RT, Wang L, Lang BT, Cregg JM, Dunbar CL, Woodward WR, Silver J, Ripplinger CM, Habecker BA - Nat Commun (2015)

Bottom Line: Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ).Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility.Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Neuroscience Graduate Program, Oregon Health and Science University, Portland, Oregon 97239, USA.

ABSTRACT
Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility. Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI. Sympathetic reinnervation prevents these changes and renders hearts remarkably resistant to induced arrhythmias.

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Absence of PTPσ restores innervation to the infarcted myocardium and prevents arrhythmias.Heart sections from HET (a) and KO (b) mice were stained for TH (green) to identify sympathetic nerve fibres and fibrinogen (red) to identify the infarct. Scale bar, 100 μm. (c) Heart rate was similar in both genotypes before (Base) and after (ISO) 10-μg ISO injection (mean±s.e.m., n=8 per genotype). (d) ISO induced comparable levels of PVCs in conscious Sham HET and KO mice; however, ISO induced significantly more PVCs in infarcted HET mice compared with KO mice and to Sham HET mice (mean±s.e.m., n=4 per group, ***P<0.001 versus HET sham and KO MI; two-way ANOVA with Bonferroni post test). (e) Fibrinogen-stained section after MI showing a transmural infarct after a 35-min occlusion. Scale bar, 500 μm. (f) Quantification of infarct size in HET and KO hearts following 35 min of occlusion (mean±s.e.m., n=4 per group; t-test, N.S. P>0.05).
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f1: Absence of PTPσ restores innervation to the infarcted myocardium and prevents arrhythmias.Heart sections from HET (a) and KO (b) mice were stained for TH (green) to identify sympathetic nerve fibres and fibrinogen (red) to identify the infarct. Scale bar, 100 μm. (c) Heart rate was similar in both genotypes before (Base) and after (ISO) 10-μg ISO injection (mean±s.e.m., n=8 per genotype). (d) ISO induced comparable levels of PVCs in conscious Sham HET and KO mice; however, ISO induced significantly more PVCs in infarcted HET mice compared with KO mice and to Sham HET mice (mean±s.e.m., n=4 per group, ***P<0.001 versus HET sham and KO MI; two-way ANOVA with Bonferroni post test). (e) Fibrinogen-stained section after MI showing a transmural infarct after a 35-min occlusion. Scale bar, 500 μm. (f) Quantification of infarct size in HET and KO hearts following 35 min of occlusion (mean±s.e.m., n=4 per group; t-test, N.S. P>0.05).

Mentions: We previously observed23 that CSPGs generated in the cardiac scar after ischaemia-reperfusion (I–R) prevented reinnervation of the infarct (Fig. 1a) despite high levels of nerve growth factor in the scar. The infarct becomes hyperinnervated in animals lacking the CSPG receptor PTPσ23 (Fig. 1b), confirming the crucial role for PTPσ in sympathetic denervation after MI. Since cardiac denervation is linked to risk for arrhythmia and cardiac arrest in human studies18192021, we asked whether restoring sympathetic innervation to the infarct and surrounding myocardium affected arrhythmia susceptibility. Control mice heterozygous for PTPσ (ptprs+/−; HET) and mice lacking PTPσ (ptprs−/−; KO) were implanted with ECG telemetry transmitters and then subjected to sham or MI surgery. Ten days after surgery, the mice were injected with 10 μg of the beta agonist isoproterenol (ISO), which has also been used to induce arrhythmias in the clinical setting25. ISO stimulated comparable increases in heart rate in all mice (Fig. 1c), but stimulated few premature ventricular complexes (PVCs) in sham mice of either genotype (Fig. 1d). In contrast, the arrhythmia response in post-MI animals differed on the basis of the innervation status of the infarct. ISO stimulated a significant number of PVCs in HET mice with denervated infarcts (Fig. 1d); however, KO mice with innervated infarcts were resistant to ISO-induced arrhythmias, having the same number of PVCs as sham animals (Fig. 1d). Infarcts were generally transmural (Fig. 1e), and infarct size was the same in both genotypes (Fig. 1f) indicating that the difference in arrhythmia susceptibility could not be explained by scar size.


Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias.

Gardner RT, Wang L, Lang BT, Cregg JM, Dunbar CL, Woodward WR, Silver J, Ripplinger CM, Habecker BA - Nat Commun (2015)

Absence of PTPσ restores innervation to the infarcted myocardium and prevents arrhythmias.Heart sections from HET (a) and KO (b) mice were stained for TH (green) to identify sympathetic nerve fibres and fibrinogen (red) to identify the infarct. Scale bar, 100 μm. (c) Heart rate was similar in both genotypes before (Base) and after (ISO) 10-μg ISO injection (mean±s.e.m., n=8 per genotype). (d) ISO induced comparable levels of PVCs in conscious Sham HET and KO mice; however, ISO induced significantly more PVCs in infarcted HET mice compared with KO mice and to Sham HET mice (mean±s.e.m., n=4 per group, ***P<0.001 versus HET sham and KO MI; two-way ANOVA with Bonferroni post test). (e) Fibrinogen-stained section after MI showing a transmural infarct after a 35-min occlusion. Scale bar, 500 μm. (f) Quantification of infarct size in HET and KO hearts following 35 min of occlusion (mean±s.e.m., n=4 per group; t-test, N.S. P>0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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f1: Absence of PTPσ restores innervation to the infarcted myocardium and prevents arrhythmias.Heart sections from HET (a) and KO (b) mice were stained for TH (green) to identify sympathetic nerve fibres and fibrinogen (red) to identify the infarct. Scale bar, 100 μm. (c) Heart rate was similar in both genotypes before (Base) and after (ISO) 10-μg ISO injection (mean±s.e.m., n=8 per genotype). (d) ISO induced comparable levels of PVCs in conscious Sham HET and KO mice; however, ISO induced significantly more PVCs in infarcted HET mice compared with KO mice and to Sham HET mice (mean±s.e.m., n=4 per group, ***P<0.001 versus HET sham and KO MI; two-way ANOVA with Bonferroni post test). (e) Fibrinogen-stained section after MI showing a transmural infarct after a 35-min occlusion. Scale bar, 500 μm. (f) Quantification of infarct size in HET and KO hearts following 35 min of occlusion (mean±s.e.m., n=4 per group; t-test, N.S. P>0.05).
Mentions: We previously observed23 that CSPGs generated in the cardiac scar after ischaemia-reperfusion (I–R) prevented reinnervation of the infarct (Fig. 1a) despite high levels of nerve growth factor in the scar. The infarct becomes hyperinnervated in animals lacking the CSPG receptor PTPσ23 (Fig. 1b), confirming the crucial role for PTPσ in sympathetic denervation after MI. Since cardiac denervation is linked to risk for arrhythmia and cardiac arrest in human studies18192021, we asked whether restoring sympathetic innervation to the infarct and surrounding myocardium affected arrhythmia susceptibility. Control mice heterozygous for PTPσ (ptprs+/−; HET) and mice lacking PTPσ (ptprs−/−; KO) were implanted with ECG telemetry transmitters and then subjected to sham or MI surgery. Ten days after surgery, the mice were injected with 10 μg of the beta agonist isoproterenol (ISO), which has also been used to induce arrhythmias in the clinical setting25. ISO stimulated comparable increases in heart rate in all mice (Fig. 1c), but stimulated few premature ventricular complexes (PVCs) in sham mice of either genotype (Fig. 1d). In contrast, the arrhythmia response in post-MI animals differed on the basis of the innervation status of the infarct. ISO stimulated a significant number of PVCs in HET mice with denervated infarcts (Fig. 1d); however, KO mice with innervated infarcts were resistant to ISO-induced arrhythmias, having the same number of PVCs as sham animals (Fig. 1d). Infarcts were generally transmural (Fig. 1e), and infarct size was the same in both genotypes (Fig. 1f) indicating that the difference in arrhythmia susceptibility could not be explained by scar size.

Bottom Line: Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ).Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility.Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Neuroscience Graduate Program, Oregon Health and Science University, Portland, Oregon 97239, USA.

ABSTRACT
Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility. Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI. Sympathetic reinnervation prevents these changes and renders hearts remarkably resistant to induced arrhythmias.

Show MeSH
Related in: MedlinePlus