Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 315, Issue 6, Pages H1821-H1834Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00245.2018
Keywords
ANA-12; brain-derived neurotrophic factor-tropomyosin-related kinase B signaling; exercise training; heart failure; tropomyosin-related kinase B blockade
Funding
- Canadian Institutes of Health Research [FRN: MOP-136923]
- Pfizer Canada
- University of Ottawa Heart Institute Foundation
- University of Ottawa Endowed Graduate Award in Cardiac Research at the Heart Institute by the University of Ottawa's Faculty of Medicine Endowed Funds in Cardiac Research
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Exercise training is beneficial for preserving cardiac function post-myocardial infarction (post-MI, but the underlying mechanisms are not well understood. We investigated one possible mechanism, brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling, with the TrkB blocker ANA-12 (0.5 mg.kg(-1).day(-1)). Male Wistar rats underwent sham surgery or ligation of the left descending coronary artery. The surviving MI rats were allocated as follows: sedentary MI. rats treated with vehicle, exercise-trained MI. rats treated with vehicle, and exercise-trained MI rats treated with ANA-12. Exercise training was done 5 days/wk. for 4 wk on a motor-driven treadmill. At the end, left ventricular (LV) function was evaluated by echocardiography and a Millar catheter. Mature BDNF and downstream effectors of BDNF-TrkB signaling, Ca-2(+)/calmodulin-dependent protein kinase II (CaMKII), Akt, and AMP-activated protein kinase (AMPK), were assessed in the noninfarct area of the LV by Western blot analysis. Exercise training increased stroke volume and cardiac index and attenuated the decrease in ejection fraction (EF) and increase in LV end-diastolic pressure post-MI. ANA-12 blocked the improvement of EF and attenuated the increases in stroke volume and cardiac index but did not affect LV end-diastolic pressure. Exercise training post-MI prevented decreases in mature BDNF, phosphorylated (p-)CaMKII, p-Akt, and p-AMPK alpha expression. These effects were all blocked by ANA-12 except for p-AMPK alpha. In conclusion, the exercise-induced improvement of EF is mediated by the BDNF-TrkB axis and the downstream effectors CaMKII and Akt. BDNF-TrkB signaling appears to contribute to the improvement in systolic function by exercise training. NEW & NOTEWORTHY Exercise training improves ejection fraction and left ventricular end-diastolic pressure (LVEDP) and increases stroke volume and cardiac index in rats postmyocardial infarction (post-MI). The improvement of EF but not LVEDP is mediated by activation of the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) axis and downstream effectors Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Akt. This suggests that activation of BDNF-TrkB signaling and CaMKII and Akt is a promising target to attenuate progressive cardiac dysfunction post-MI.
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