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Pigment Epithelium ‐ Derived Factor ( PEDF ) Improves Ischemic Cardiac Functional Reserve Through Decreasing Hypoxic Cardiomyocyte Contractility Through PEDF Receptor ( PEDF ‐ R)

View Article: PubMed Central - PubMed

ABSTRACT

Background: Pigment epithelium‐derived factor (PEDF), which belongs to the noninhibitory serpin family, has shown the ability to stimulate several physiological processes, such as antiangiogenesis, anti‐inflammation, and antioxidation. In the present study, the effects of PEDF on contractility and calcium handling of rat ventricular myocytes were investigated.

Methods and results: Adult Sprague‐Dawley rat models of acute myocardial infarction (AMI) were surgically established. PEDF‐lentivirus was delivered into the myocardium along and away from the infarction border to overexpress PEDF. Video edge detection was used to measure myocyte shortening in vitro. Intracellular Ca2+ was measured in cells loaded with the Ca2+ sensitive fluorescent indicator, Fura‐2‐acetoxymethyl ester. PEDF local overexpression enhanced cardiac functional reserve in AMI rats and reduced myocardial contracture bordering the infracted area. Exogenous PEDF treatment (10 nmol/L) caused a significant decrease in amplitudes of isoproterenol‐stimulated myocyte shortening, Ca2+ transients, and caffeine‐evoked Ca2+ transients in vitro. We then tested a potential role for PEDF receptor‐mediated effects on upregulation of protein kinase C (PKC) and found evidence of signaling through the diacylglycerol/PKCα pathway. We also confirmed that pretreatment of cardiomyocytes with PEDF exhibited dephosphorylation of phospholamban at Ser16, which could be attenuated with PKC inhibition.

Conclusions: The results suggest that PEDF depresses myocyte contractility by suppressing phosphorylation of phospholamban and Ca2+ transients in a PKCα‐dependent manner through its receptor, PEDF receptor, therefore improving cardiac functional reserve during AMI.

No MeSH data available.


Related in: MedlinePlus

Evaluation of cardiac functional reserve after acute myocardial infarction (AMI). Cardiac function was measured in pigment epithelium‐derived factor (PEDF)‐transfected myocardial infarction (MI) hearts using transthoracic M‐mode echocardiography. Measurements were performed in rats before injection of dobutamine (1 μg/g) and 10 minutes after injection at 2 weeks post‐AMI. The 2 groups included vector transfected rats (MI) and PEDF‐transfected rats (PEDF). A, Representative echocardiograms of an MI rat before and after dobutamine injection. B, Representative echocardiograms of a PEDF‐transfected rat before and after dobutamine injection. C, Delta left ventricular ejection fraction. D, Delta left ventricular fractional shortening. E, Delta left ventricular cardiac output. F, Representative images of 2,3,5‐triphenyltetrazolium‐stained myocardial tissues. G, Quantification of infarct size. Data are shown as mean±SE from 7 hearts (n=7). *P<0.05 versus MI; **P<0.01 versus MI. Results show that PEDF significantly improved cardiac functional reserve and reduced myocardial infarct size when compared to the MI group.
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jah31649-fig-0002: Evaluation of cardiac functional reserve after acute myocardial infarction (AMI). Cardiac function was measured in pigment epithelium‐derived factor (PEDF)‐transfected myocardial infarction (MI) hearts using transthoracic M‐mode echocardiography. Measurements were performed in rats before injection of dobutamine (1 μg/g) and 10 minutes after injection at 2 weeks post‐AMI. The 2 groups included vector transfected rats (MI) and PEDF‐transfected rats (PEDF). A, Representative echocardiograms of an MI rat before and after dobutamine injection. B, Representative echocardiograms of a PEDF‐transfected rat before and after dobutamine injection. C, Delta left ventricular ejection fraction. D, Delta left ventricular fractional shortening. E, Delta left ventricular cardiac output. F, Representative images of 2,3,5‐triphenyltetrazolium‐stained myocardial tissues. G, Quantification of infarct size. Data are shown as mean±SE from 7 hearts (n=7). *P<0.05 versus MI; **P<0.01 versus MI. Results show that PEDF significantly improved cardiac functional reserve and reduced myocardial infarct size when compared to the MI group.

Mentions: Of the 14 rats entered into the present experiment, they were divided into PEDF or vehicle treatment groups. We first examined expression of PEDF and PEDF‐R after 2 weeks of MI (Figure 1A). Results showed that protein levels of PEDF decreased and protein levels of PEDF‐R increased 2 weeks post‐AMI (Figure 1B and 1C). Then, the PEDF‐LV was successfully transfected into myocardium and confirmed by its green fluorescent protein (GFP) fluorescence (Figure 1D). ELISA analysis showed that protein levels of PEDF in the PEDF‐transfected group significantly increased compared to those of the control group and could reach up to 9.55 nmol/L (Figure 1E). Cardiac contractile function was measured at 2 weeks post‐MI using transthoracic M‐mode echocardiography before and after dobutamine (1 μg/g) injection (Figure 2A and 2B). The delta ejection fraction (ΔEF) and delta fractional shortening to dobutamine infusions were both significantly higher in hearts transfected with PEDF compared to untreated MI hearts (Figure 2C and 2D). Evaluation of cardiac reserve (stress‐rest) clearly indicated that PEDF treatment had increased delta CO, compared to the MI group, during dobutamine challenge (Figure 2E). In addition, PEDF treatment also showed reduced myocardial infarct size compared to the vector control in AMI rats (Figure 2F and 2G).


Pigment Epithelium ‐ Derived Factor ( PEDF ) Improves Ischemic Cardiac Functional Reserve Through Decreasing Hypoxic Cardiomyocyte Contractility Through PEDF Receptor ( PEDF ‐ R)
Evaluation of cardiac functional reserve after acute myocardial infarction (AMI). Cardiac function was measured in pigment epithelium‐derived factor (PEDF)‐transfected myocardial infarction (MI) hearts using transthoracic M‐mode echocardiography. Measurements were performed in rats before injection of dobutamine (1 μg/g) and 10 minutes after injection at 2 weeks post‐AMI. The 2 groups included vector transfected rats (MI) and PEDF‐transfected rats (PEDF). A, Representative echocardiograms of an MI rat before and after dobutamine injection. B, Representative echocardiograms of a PEDF‐transfected rat before and after dobutamine injection. C, Delta left ventricular ejection fraction. D, Delta left ventricular fractional shortening. E, Delta left ventricular cardiac output. F, Representative images of 2,3,5‐triphenyltetrazolium‐stained myocardial tissues. G, Quantification of infarct size. Data are shown as mean±SE from 7 hearts (n=7). *P<0.05 versus MI; **P<0.01 versus MI. Results show that PEDF significantly improved cardiac functional reserve and reduced myocardial infarct size when compared to the MI group.
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getmorefigures.php?uid=PMC5015364&req=5

jah31649-fig-0002: Evaluation of cardiac functional reserve after acute myocardial infarction (AMI). Cardiac function was measured in pigment epithelium‐derived factor (PEDF)‐transfected myocardial infarction (MI) hearts using transthoracic M‐mode echocardiography. Measurements were performed in rats before injection of dobutamine (1 μg/g) and 10 minutes after injection at 2 weeks post‐AMI. The 2 groups included vector transfected rats (MI) and PEDF‐transfected rats (PEDF). A, Representative echocardiograms of an MI rat before and after dobutamine injection. B, Representative echocardiograms of a PEDF‐transfected rat before and after dobutamine injection. C, Delta left ventricular ejection fraction. D, Delta left ventricular fractional shortening. E, Delta left ventricular cardiac output. F, Representative images of 2,3,5‐triphenyltetrazolium‐stained myocardial tissues. G, Quantification of infarct size. Data are shown as mean±SE from 7 hearts (n=7). *P<0.05 versus MI; **P<0.01 versus MI. Results show that PEDF significantly improved cardiac functional reserve and reduced myocardial infarct size when compared to the MI group.
Mentions: Of the 14 rats entered into the present experiment, they were divided into PEDF or vehicle treatment groups. We first examined expression of PEDF and PEDF‐R after 2 weeks of MI (Figure 1A). Results showed that protein levels of PEDF decreased and protein levels of PEDF‐R increased 2 weeks post‐AMI (Figure 1B and 1C). Then, the PEDF‐LV was successfully transfected into myocardium and confirmed by its green fluorescent protein (GFP) fluorescence (Figure 1D). ELISA analysis showed that protein levels of PEDF in the PEDF‐transfected group significantly increased compared to those of the control group and could reach up to 9.55 nmol/L (Figure 1E). Cardiac contractile function was measured at 2 weeks post‐MI using transthoracic M‐mode echocardiography before and after dobutamine (1 μg/g) injection (Figure 2A and 2B). The delta ejection fraction (ΔEF) and delta fractional shortening to dobutamine infusions were both significantly higher in hearts transfected with PEDF compared to untreated MI hearts (Figure 2C and 2D). Evaluation of cardiac reserve (stress‐rest) clearly indicated that PEDF treatment had increased delta CO, compared to the MI group, during dobutamine challenge (Figure 2E). In addition, PEDF treatment also showed reduced myocardial infarct size compared to the vector control in AMI rats (Figure 2F and 2G).

View Article: PubMed Central - PubMed

ABSTRACT

Background: Pigment epithelium&#8208;derived factor (PEDF), which belongs to the noninhibitory serpin family, has shown the ability to stimulate several physiological processes, such as antiangiogenesis, anti&#8208;inflammation, and antioxidation. In the present study, the effects of PEDF on contractility and calcium handling of rat ventricular myocytes were investigated.

Methods and results: Adult Sprague&#8208;Dawley rat models of acute myocardial infarction (AMI) were surgically established. PEDF&#8208;lentivirus was delivered into the myocardium along and away from the infarction border to overexpress PEDF. Video edge detection was used to measure myocyte shortening in&nbsp;vitro. Intracellular Ca2+ was measured in cells loaded with the Ca2+ sensitive fluorescent indicator, Fura&#8208;2&#8208;acetoxymethyl ester. PEDF local overexpression enhanced cardiac functional reserve in AMI rats and reduced myocardial contracture bordering the infracted area. Exogenous PEDF treatment (10&nbsp;nmol/L) caused a significant decrease in amplitudes of isoproterenol&#8208;stimulated myocyte shortening, Ca2+ transients, and caffeine&#8208;evoked Ca2+ transients in&nbsp;vitro. We then tested a potential role for PEDF receptor&#8208;mediated effects on upregulation of protein kinase C (PKC) and found evidence of signaling through the diacylglycerol/PKC&alpha; pathway. We also confirmed that pretreatment of cardiomyocytes with PEDF exhibited dephosphorylation of phospholamban at Ser16, which could be attenuated with PKC inhibition.

Conclusions: The results suggest that PEDF depresses myocyte contractility by suppressing phosphorylation of phospholamban and Ca2+ transients in a PKC&alpha;&#8208;dependent manner through its receptor, PEDF receptor, therefore improving cardiac functional reserve during AMI.

No MeSH data available.


Related in: MedlinePlus