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Brain-derived neurotrophic factor regulates TRPC3/6 channels and protects against myocardial infarction in rodents.

Hang P, Zhao J, Cai B, Tian S, Huang W, Guo J, Sun C, Li Y, Du Z - Int. J. Biol. Sci. (2015)

Bottom Line: Meanwhile, echocardiography indicated that BDNF significantly improved cardiac function of MI mice.Furthermore, protective role of BDNF against hypoxia-induced apoptosis was reversed by 2-APB and TRPC3/6 siRNAs.BDNF/TrkB alleviated cardiac ischemic injury and inhibited cardiomyocytes apoptosis by regulating TRPC3/6 channels, which provides a novel potential therapeutic candidate for MI.

View Article: PubMed Central - PubMed

Affiliation: 1. Institute of Clinical Pharmacology of the Second Affiliated Hospital (Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions), Harbin Medical University, Harbin 150086, China.

ABSTRACT

Background: Brain-derived neurotrophic factor (BDNF) is associated with coronary artery diseases. However, its role and mechanism in myocardial infarction (MI) is not fully understood.

Methods: Wistar rat and Kunming mouse model of MI were induced by the ligation of left coronary artery. Blood samples were collected from MI rats and patients. Plasma BDNF level, protein expression of BDNF, tropomyosin-related kinase B (TrkB) and its downstream transient receptor potential canonical (TRPC)3/6 channels were examined by enzyme-linked immunosorbent assay and Western blot. Infarct size, cardiac function and cardiomyocyte apoptosis were measured after intra-myocardium injection with recombinant human BDNF. Protective role of BDNF against cardiomyocyte apoptosis was confirmed by BDNF scavenger TrkB-Fc. The regulation of TRPC3/6 channels by BDNF was validated by pretreating with TRPC blocker (2-Aminoethyl diphenylborinate, 2-APB) and TRPC3/6 siRNAs.

Results: Circulating BDNF was significantly enhanced in MI rats and patients. Protein expression of BDNF, TrkB and TRPC3/6 channels were upregulated in MI. 3 days post-MI, BDNF treatment markedly reduced the infarct size and serum lactate dehydrogenase activity. Meanwhile, echocardiography indicated that BDNF significantly improved cardiac function of MI mice. Furthermore, BDNF markedly inhibited cardiomyocyte apoptosis by upregulating Bcl-2 expression and downregulating caspase-3 expression and activity in ischemic myocardium. In neonatal rat ventricular myocytes, cell viability was dramatically increased by BDNF in hypoxia, which was restored by TrkB-Fc. Furthermore, protective role of BDNF against hypoxia-induced apoptosis was reversed by 2-APB and TRPC3/6 siRNAs.

Conclusion: BDNF/TrkB alleviated cardiac ischemic injury and inhibited cardiomyocytes apoptosis by regulating TRPC3/6 channels, which provides a novel potential therapeutic candidate for MI.

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Effect of BDNF on cardiac infarct area, lactate dehydrogenase (LDH) activity and cardiomyocyte apoptosis in mice 3 days post-MI. (A) Representative images showing infarct areas in cross section slices, scale bar: 5 mm; (B) Statistical analysis of IA/AAR ratio. IA, infarct area; AAR, area at risk. Data are expressed as mean ± SEM; *p<0.05 vs. MI, n = 4 mice each group. (C) Serum LDH activity in MI and BDNF pretreated mice. ***p<0.001 vs. sham, ###p<0.001 vs. MI, n = 4 mice each group. (D) Effect of BDNF on cardiomyocytes apoptosis 3 days post-MI by TUNEL staining, scale bar: 200 μm. (E) TUNEL positive cell (%). **p<0.01 vs. sham, ##p<0.01 vs. MI, n = 5 mice each group.
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Figure 5: Effect of BDNF on cardiac infarct area, lactate dehydrogenase (LDH) activity and cardiomyocyte apoptosis in mice 3 days post-MI. (A) Representative images showing infarct areas in cross section slices, scale bar: 5 mm; (B) Statistical analysis of IA/AAR ratio. IA, infarct area; AAR, area at risk. Data are expressed as mean ± SEM; *p<0.05 vs. MI, n = 4 mice each group. (C) Serum LDH activity in MI and BDNF pretreated mice. ***p<0.001 vs. sham, ###p<0.001 vs. MI, n = 4 mice each group. (D) Effect of BDNF on cardiomyocytes apoptosis 3 days post-MI by TUNEL staining, scale bar: 200 μm. (E) TUNEL positive cell (%). **p<0.01 vs. sham, ##p<0.01 vs. MI, n = 5 mice each group.

Mentions: We next detected the functional role of BDNF in infarct heart, and found that BDNF could significantly reduce the infarct size in MI (Fig. 5A, B). LDH is a important marker for cardiac injury, therefore, serum LDH activity was further detected. We found that serum LDH activity was increased at 3 days post-MI, and was significantly decreased by BDNF (Fig. 5C). Thus, BDNF displayed protective effect against ischemic-injury.


Brain-derived neurotrophic factor regulates TRPC3/6 channels and protects against myocardial infarction in rodents.

Hang P, Zhao J, Cai B, Tian S, Huang W, Guo J, Sun C, Li Y, Du Z - Int. J. Biol. Sci. (2015)

Effect of BDNF on cardiac infarct area, lactate dehydrogenase (LDH) activity and cardiomyocyte apoptosis in mice 3 days post-MI. (A) Representative images showing infarct areas in cross section slices, scale bar: 5 mm; (B) Statistical analysis of IA/AAR ratio. IA, infarct area; AAR, area at risk. Data are expressed as mean ± SEM; *p<0.05 vs. MI, n = 4 mice each group. (C) Serum LDH activity in MI and BDNF pretreated mice. ***p<0.001 vs. sham, ###p<0.001 vs. MI, n = 4 mice each group. (D) Effect of BDNF on cardiomyocytes apoptosis 3 days post-MI by TUNEL staining, scale bar: 200 μm. (E) TUNEL positive cell (%). **p<0.01 vs. sham, ##p<0.01 vs. MI, n = 5 mice each group.
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Figure 5: Effect of BDNF on cardiac infarct area, lactate dehydrogenase (LDH) activity and cardiomyocyte apoptosis in mice 3 days post-MI. (A) Representative images showing infarct areas in cross section slices, scale bar: 5 mm; (B) Statistical analysis of IA/AAR ratio. IA, infarct area; AAR, area at risk. Data are expressed as mean ± SEM; *p<0.05 vs. MI, n = 4 mice each group. (C) Serum LDH activity in MI and BDNF pretreated mice. ***p<0.001 vs. sham, ###p<0.001 vs. MI, n = 4 mice each group. (D) Effect of BDNF on cardiomyocytes apoptosis 3 days post-MI by TUNEL staining, scale bar: 200 μm. (E) TUNEL positive cell (%). **p<0.01 vs. sham, ##p<0.01 vs. MI, n = 5 mice each group.
Mentions: We next detected the functional role of BDNF in infarct heart, and found that BDNF could significantly reduce the infarct size in MI (Fig. 5A, B). LDH is a important marker for cardiac injury, therefore, serum LDH activity was further detected. We found that serum LDH activity was increased at 3 days post-MI, and was significantly decreased by BDNF (Fig. 5C). Thus, BDNF displayed protective effect against ischemic-injury.

Bottom Line: Meanwhile, echocardiography indicated that BDNF significantly improved cardiac function of MI mice.Furthermore, protective role of BDNF against hypoxia-induced apoptosis was reversed by 2-APB and TRPC3/6 siRNAs.BDNF/TrkB alleviated cardiac ischemic injury and inhibited cardiomyocytes apoptosis by regulating TRPC3/6 channels, which provides a novel potential therapeutic candidate for MI.

View Article: PubMed Central - PubMed

Affiliation: 1. Institute of Clinical Pharmacology of the Second Affiliated Hospital (Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions), Harbin Medical University, Harbin 150086, China.

ABSTRACT

Background: Brain-derived neurotrophic factor (BDNF) is associated with coronary artery diseases. However, its role and mechanism in myocardial infarction (MI) is not fully understood.

Methods: Wistar rat and Kunming mouse model of MI were induced by the ligation of left coronary artery. Blood samples were collected from MI rats and patients. Plasma BDNF level, protein expression of BDNF, tropomyosin-related kinase B (TrkB) and its downstream transient receptor potential canonical (TRPC)3/6 channels were examined by enzyme-linked immunosorbent assay and Western blot. Infarct size, cardiac function and cardiomyocyte apoptosis were measured after intra-myocardium injection with recombinant human BDNF. Protective role of BDNF against cardiomyocyte apoptosis was confirmed by BDNF scavenger TrkB-Fc. The regulation of TRPC3/6 channels by BDNF was validated by pretreating with TRPC blocker (2-Aminoethyl diphenylborinate, 2-APB) and TRPC3/6 siRNAs.

Results: Circulating BDNF was significantly enhanced in MI rats and patients. Protein expression of BDNF, TrkB and TRPC3/6 channels were upregulated in MI. 3 days post-MI, BDNF treatment markedly reduced the infarct size and serum lactate dehydrogenase activity. Meanwhile, echocardiography indicated that BDNF significantly improved cardiac function of MI mice. Furthermore, BDNF markedly inhibited cardiomyocyte apoptosis by upregulating Bcl-2 expression and downregulating caspase-3 expression and activity in ischemic myocardium. In neonatal rat ventricular myocytes, cell viability was dramatically increased by BDNF in hypoxia, which was restored by TrkB-Fc. Furthermore, protective role of BDNF against hypoxia-induced apoptosis was reversed by 2-APB and TRPC3/6 siRNAs.

Conclusion: BDNF/TrkB alleviated cardiac ischemic injury and inhibited cardiomyocytes apoptosis by regulating TRPC3/6 channels, which provides a novel potential therapeutic candidate for MI.

Show MeSH
Related in: MedlinePlus