Jacob Schneiderman

Plasminogen activator inhibitors

Plasminogen activator inhibitors (PAIs) regulate plasminogen activation in normal and pathologic processes. Plasminogen activator inhibitor 1 (PAI-1) is the major physiologic inhibitor of both tissue-type and urokinase-type plasminogen activators. It is a highly regulated single-chain glycoprotein, whose overexpression in vivo impairs the fibrinolytic balance and correlates with thrombotic disorders. Recent clinical observations suggest an association between elevated plasma PAI-1 and symptomatic coronary artery occlusive disease or deep venous thrombosis. Recognition of the clinical relevance of PAIs and timely assessment of the fibrinolytic capacity in patients at risk may have therapeutic implications.

Modulation of the fibrinolytic system by major peripheral ischemia

PURPOSEnA rat model was developed to investigate the effects of acute peripheral ischemia on the components of the fibrinolytic system.nnnMETHODSnLaparotomy was performed and ischemia was introduced by total aortic clamping at a subrenal position. Control animals underwent sham laparotomy alone. Plasma and tissue samples were collected for analysis at 30, 60, 90, and 120 minutes after operation.nnnRESULTSnFunctional assays of rat plasma revealed a dramatic and transient increase in tissue-type plasminogen activator (tPA) activity within 30 minutes of the onset of ischemia. A simultaneous decline in plasminogen activator inhibitor activity was observed. Immunohistochemical analysis suggested this initial increase in tPA activity resulted primarily from the release of stored tPA from ischemic vascular tissues. Northern blot analysis revealed that both tPA and plasminogen activator inhibitor-1 messenger RNA levels were elevated at 60 to 120 minutes in well-perfused tissues distant from the ischemic insult.nnnCONCLUSIONSnCollectively, these data demonstrate that acute peripheral ischemia results in a rapid and transient increase in plasma fibrinolytic activity, concomitant with the early release of stored tPA from ischemic vascular tissues. In addition, peripheral ischemia appears to stimulate both tPA and plasminogen activator inhibitor-1 gene expression in well-perfused tissues at later time points, consistent with the existence of humoral mediators.

Cardiac leptin overexpression in the context of acute MI and reperfusion potentiates myocardial remodeling and left ventricular dysfunction

Background Acute MI induces leptin expression in the heart, however the role of myocardial leptin in cardiac ischemia and reperfusion (IR) remains unknown. To shed light on the effects of elevated levels of leptin in the myocardium, we overexpressed cardiac leptin and assessed local remodeling and myocardial function in this context. Methods and results Cardiac leptin overexpression was stimulated in mice undergoing IR by a single intraperitoneal injection of leptin antagonist (LepA). All mice exhibited a normal pattern of body weight gain. A rapid, long-term upregulation of leptin mRNA was demonstrated in the heart, adipose, and liver tissues in IR/LepA-treated mice. Overexpressed cardiac leptin mRNA extended beyond postoperative day (POD) 30. Plasma leptin peaked 7.5 hours postoperatively, especially in IR/LepA-treated mice, subsiding to normal levels by 24 hours. On POD-30 IR/LepA-treated mice demonstrated cardiomyocyte hypertrophy and perivascular fibrosis compared to IR/saline controls. Echocardiography on POD-30 demonstrated eccentric hypertrophy and systolic dysfunction in IR/LepA. We recorded reductions in Ejection Fraction (p<0.001), Fraction Shortening (p<0.01), and Endocardial Fraction Area Change (p<0.01), and an increase in Endocardial Area Change (p<0.01). Myocardial remodeling in the context of IR and cardiac leptin overexpression was associated with increased cardiac TGFβ ligand expression, activated Smad2, and downregulation of STAT3 activity. Conclusions Cardiac IR coinciding with increased myocardial leptin synthesis promotes cardiomyocyte hypertrophy and fibrosis and potentiates myocardial dysfunction. Plasma leptin levels do not reflect cardiac leptin synthesis, and may not predict leptin-related cardiovascular morbidity. Targeting cardiac leptin is a potential treatment for cardiac IR damage.