Abstract
Background: Secreted frizzled-related protein 5 (Sfrp5) has been suggested to be a protective regulatory protein in coronary heart disease. However, the role of Sfrp5 in regulating ischemic injury and its consequences is not known. The aim of our study was to explore the effects of Sfrp5 on hearts after myocardial infarction (MI) and to investigate the underlying mechanisms.Methods and Results: We found that Sfrp5 was downregulated over time in the heart tissue of MI mice. To further elucidate the role of Sfrp5 during MI, we established a cardiac overexpression of an Sfrp5 mouse model using the cardiotropic adeno-associated virus serotype 9 (AAV9). Overexpression of Sfrp5 significantly reduced infarct size as demonstrated by a decrease in mortality owing to cardiac rupture. Moreover, cardiac overexpression of Sfrp5 increased left ventricular function and mitochondrial biogenesis, decreased cardiomyocyte apoptosis, suppressed inflammation reaction, inhibited oxidative stress, and ameliorated cardiac remodeling as demonstrated by left ventricular ejection fraction, mitochondrial morphology, heart weight, NADH oxidase activity levels, and myocardial fibrosis at 2 weeks post-MI. At the molecular level, overexpression of Sfrp5 significantly increased the expression of p-AMPKThr172 protein with higher expression of mitochondrial fusion protein (MFN1 and MFN2) and lower expression of mitochondrial fission protein (p-Drp1Ser616/Mid49/MFF/Fis-1). In isolated neonatal rat cardiac myocytes, Sfrp5 treatment attenuated hypoxia-induced mitochondrial dysfunction. Inhibition of AMPK activity with compound C abrogated this benefit.Conclusions: Sfrp5 overexpression inhibits ischemic injury, reduces risk of cardiac rupture, ameliorates post-MI remodeling, and decreases the progression to heart failure via disrupting mitochondrial dysfunction and partly through normalizing the AMPK activity.
Highlights
Cardiovascular disease is the leading cause of death and disability in the world [1]
To elucidate whether Secreted frizzled-related protein 5 (Sfrp5) was detrimental or beneficial for post-Myocardial infarction (MI) cardiac injury, Sfrp5 overexpression was induced in mice by intravenous injection of Associated Virus Serotype 9 (AAV9)-Sfrp5 or AAV9-NC through the tail vein 4 weeks before MI or sham operation (Figure 2A)
The results showed that Sfrp5 decreased mitochondrial fragmentation, while inhibition of AMPK with compound C abolished the benefits of Sfrp5-induced mitochondrial protection under hypoxia (Figures 6C,D)
Summary
Cardiovascular disease is the leading cause of death and disability in the world [1]. Myocardial infarction (MI) is a major event of cardiovascular disease and associated with high morbidity. MI causes excessive loss of cardiac myocytes, and a progressive cardiac remodeling results in cardiac dysfunction and heart failure (HF) [2]. The pathogenesis of MI is multifactorial, mitochondrial dysfunction is thought to be one of the major causes [3]. Mitochondria as an organelle for translating energy can regulate metabolism and ATP production and sustain cardiomyocyte contractility and function in normal myocardial tissue [4]. In pathological condition, impaired mitochondria alter cardiac energy metabolism, decrease cardiac efficiency, and worsen the progression of cardiac remodeling [5]. The aim of our study was to explore the effects of Sfrp on hearts after myocardial infarction (MI) and to investigate the underlying mechanisms
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
