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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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Sympathetic innervation of the infarct prevents β-AR supersensitivity.(a) APD90 maps before (Baseline) and after 1-μM ISO (100-ms pacing interval or 600 b.p.m. heart rate for each condition), and representative traces of optical action potentials from sites marked with *. Scale bar, 50 ms. (b) Percent change in APD90 following ISO treatment (mean±s.e.m.; n=4–5 hearts per group; **P<0.01 by two-way ANOVA with Bonferroni post test). (c) IQR of APD90 following ISO treatment (mean±s.e.m.; n=4–5 hearts; **P<0.01 by two-way ANOVA with Bonferroni post test).
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f4: Sympathetic innervation of the infarct prevents β-AR supersensitivity.(a) APD90 maps before (Baseline) and after 1-μM ISO (100-ms pacing interval or 600 b.p.m. heart rate for each condition), and representative traces of optical action potentials from sites marked with *. Scale bar, 50 ms. (b) Percent change in APD90 following ISO treatment (mean±s.e.m.; n=4–5 hearts per group; **P<0.01 by two-way ANOVA with Bonferroni post test). (c) IQR of APD90 following ISO treatment (mean±s.e.m.; n=4–5 hearts; **P<0.01 by two-way ANOVA with Bonferroni post test).

Mentions: Sudden cardiac death is most common in the morning35, when circulating catecholamines (NE and epinephrine) are rising rapidly36. Given the protective role of beta blockers in humans, and the observation that PVCs induced by the beta agonist ISO are a good marker of arrhythmia propensity in humans25, we examined the role of β-AR activation in arrhythmia generation in our infarcted mouse hearts. We treated hearts with tyramine to induce the release of endogenous NE from sympathetic axons within the heart, and with ISO to mimic circulating catecholamines. Release of endogenous NE with tyramine resulted in similar APD shortening across all groups (% change: HET Sham −0.5±0.6, HET MI −0.8±0.6, KO Sham −0.2±0.2, KO MI −2.1±0.6; n=3–5, mean±s.e.m.). In contrast, treatment with ISO, which mimics the effect of circulating catecholamines in vivo, stimulated a significantly greater shortening of APD90 in denervated HET MI hearts compared with all other groups (Fig. 4a,b). This denervation-induced β-AR supersensitivity is consistent with recent human data21. Consistent with the baseline data, APD90 dispersion (IQR) remained elevated in the HET MI hearts following ISO treatment (Fig. 4c).


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)

Sympathetic innervation of the infarct prevents β-AR supersensitivity.(a) APD90 maps before (Baseline) and after 1-μM ISO (100-ms pacing interval or 600 b.p.m. heart rate for each condition), and representative traces of optical action potentials from sites marked with *. Scale bar, 50 ms. (b) Percent change in APD90 following ISO treatment (mean±s.e.m.; n=4–5 hearts per group; **P<0.01 by two-way ANOVA with Bonferroni post test). (c) IQR of APD90 following ISO treatment (mean±s.e.m.; n=4–5 hearts; **P<0.01 by two-way ANOVA with Bonferroni post test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4315356&req=5

f4: Sympathetic innervation of the infarct prevents β-AR supersensitivity.(a) APD90 maps before (Baseline) and after 1-μM ISO (100-ms pacing interval or 600 b.p.m. heart rate for each condition), and representative traces of optical action potentials from sites marked with *. Scale bar, 50 ms. (b) Percent change in APD90 following ISO treatment (mean±s.e.m.; n=4–5 hearts per group; **P<0.01 by two-way ANOVA with Bonferroni post test). (c) IQR of APD90 following ISO treatment (mean±s.e.m.; n=4–5 hearts; **P<0.01 by two-way ANOVA with Bonferroni post test).
Mentions: Sudden cardiac death is most common in the morning35, when circulating catecholamines (NE and epinephrine) are rising rapidly36. Given the protective role of beta blockers in humans, and the observation that PVCs induced by the beta agonist ISO are a good marker of arrhythmia propensity in humans25, we examined the role of β-AR activation in arrhythmia generation in our infarcted mouse hearts. We treated hearts with tyramine to induce the release of endogenous NE from sympathetic axons within the heart, and with ISO to mimic circulating catecholamines. Release of endogenous NE with tyramine resulted in similar APD shortening across all groups (% change: HET Sham −0.5±0.6, HET MI −0.8±0.6, KO Sham −0.2±0.2, KO MI −2.1±0.6; n=3–5, mean±s.e.m.). In contrast, treatment with ISO, which mimics the effect of circulating catecholamines in vivo, stimulated a significantly greater shortening of APD90 in denervated HET MI hearts compared with all other groups (Fig. 4a,b). This denervation-induced β-AR supersensitivity is consistent with recent human data21. Consistent with the baseline data, APD90 dispersion (IQR) remained elevated in the HET MI hearts following ISO treatment (Fig. 4c).

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