Cardioprotection by polysaccharide sulfate against ischemia/reperfusion injury in isolated rat hearts.
OBJECTIVE
Polysaccharide sulfate (PSS) is a new type of heparinoid synthesized with alginic acid as the basic material and then by chemical introduction of effective groups. Although PSS is successfully applied in ischemic cardio-cerebrovascular disease, its effect on cardiac function after ischemia/reperfusion (I/R) injury has previously not been investigated. The aim of the present study was to investigate whether PSS can protect the heart from I/R injury and the underlying mechanism of protection.


METHODS
Isolated rat hearts were perfused (Langendorff) and subjected to 20 min global ischemia followed by 60 min reperfusion with Kreb's Henseleit solution or PSS (0.3-100 mg/L). Myocardial contractile function was continuously recorded. Creatine kinase (CK) and lactate dehydrogenase (LDH) leakage were measured. Tumor necrosis factor-alpha (TNF-alpha) expression in cardiomyocytes was investigated. Western blot analysis for extracellular regulated kinases (ERKs), c-jun amino-terminal kinase (JNKs) and p38 mitogen-activated protein kinase (MAPK) activity was performed.


RESULTS
After I/R, cardiac contractility decreased, CK and LDH levels increased in the coronary effluent, and TNF-alpha expression increased in cardiomyocytes. PSS administration at concentrations of 1-30 mg/L improved cardiac contractility, reduced CK and LDH release and inhibited TNF-alpha production. Phosphorylated-p38MAPK (p-p38MAPK) and p-p54/p46-JNK increased in I/R rat hearts but diminished in PSS (1-30 mg/L) treated hearts. P-p44/p42-ERK levels were unchanged. In contrast, high concentrations of PSS (100 mg/L) had adverse effects that caused a worsening of heart function.


CONCLUSIONS
PSS has dose-dependent cardioprotective effects on the rat heart after I/R injury. The beneficial effects may be mediated through normalization of the activity of p38 MAPK and JNK pathways as well as controlling the level of TNF-alpha expression.
Yang
Ying
Y
Institute of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
Hu
Shen-jiang
SJ
Li
Liang
L
Chen
Guo-ping
GP
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003402:Creatine Kinase / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D011134:Polysaccharides / Q000737:chemistry / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control*; D013431:Sulfates / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002316:Cardiotonic Agents; D011134:Polysaccharides; D013431:Sulfates; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003402:Creatine Kinase