Sobel Lab Research

Area of interest

• Diabetes and Heart Failure.

Work in our group focusing on thrombosis and fibrinolysis has led to the publication of more than 575 peer reviewed manuscripts in prestigious journals. Its scope and direction can probably best be described with respect to an odyssey outlined in the paragraphs that follow.

We have recently published a report in Circulation (1) showing that: 1) diabetes impairs the fibrinolytic system and hence constrains the dissolution of blood clots that precipitate heart attacks; and 2) treatment of patients with a novel class of anti-diabetic pharmacologic agents, insulin sensitizers, ameliorates the impairment. Taken together these observations may well shape the manner in which people with type 2 diabetes are treated.

More than 20 years ago I was seared emotionally by being with a courageous, then young, daughter of a world renowned colleague. She was going blind secondary to diabetes. The experience led to a quest to answer the question of why diabetes leads to degradation of the vasculature that underlies accelerated coronary artery disease and heart failure. Previously, we had worked on dissolving coronary clots in patients with tissue-type plasminogen activator (t-PA), an ultimately fruitful advance (2). We had learned about inhibitors of the clot dissolving system (fibrinolytic system) such as plasminogen activator inhibitor type-1 (PAI-1). Stimulated by the emotionally searing experience mentioned we made numerous observations pertinent to the impact of diabetes on the fibrinolytic system.

In type 2 diabetes, hyperinsulinemia is present for decades because of resistance to insulin by liver, skeletal muscle, and fat and consequent compensatory increased elaboration of insulin from pancreatic beta cells into the circulating blood. In type 1 diabetes tissues are exposed to high concentrations of exogenous insulin administered for control of hyperglycemia. Thus, in both, hyperinsulinemia is prominent and prolonged. We found that diverse types of cells in culture exhibited markedly increased synthesis and elaboration of PAI-1 in response to insulin consistent with the view that compensatory hyperinsulinemia was deranging the fibrinolytic system in people with diabetes by increasing expression of PAI-1. We have shown the following: 1) increased PAI-1 in vessel walls of experimental animals is pro-atherogenic; 2) in blood it is pro-thrombotic; 3) it is induced by insulin resistance; 4) it accompanies insulin resistance of diverse etiologies in patients; 5) it is inducible also by mimicking the metabolic features of type 2 diabetes in normal human subjects; 6) it increases fibrosis in the heart undergoing infarction in experimental animals potentially exacerbating heart failure; 7) it accelerates evolution of atherosclerotic coronary plaques vulnerable to rupture and hence to precipitating acute coronary syndromes; and 8) that it is therefore an attractive target for amelioration pharmacologically in patients with diabetes.

Predicated on these and other observations, we undertook a collaboration with the Bypass Angioplasty Revascularization Investigation (BARI) investigators. A new BARI trial was being designed to determine whether early mechanical or surgical coronary revascularization would be beneficial in patients with diabetes without clinically progressive coronary artery disease. We had found that a class of pharmacologic agents called insulin sensitizers exerted favorable effects on the imbalance between fibrinolysis and thrombosis first in experimental animals and subsequently in patients with diabetes. We sought to compare effects on PAI-1 of the insulin sensitizers and insulin providing agents in the trial being designed. Ultimately, the BARI 2D (type 2 diabetes) trial was undertaken, and the acquisition of data and analysis in our laboratory of more than 50,000 blood samples (in duplicate) from 2368 patients in more than 125 clinical centers throughout the world were initiated.

The data in the manuscript published recently in Circulation (1) and the supplemental material available on line demonstrate that insulin sensitization exerts favorable effects in ameliorating the impairment of fibrinolysis and that the effects are sustained over an approximately 5-year period of overall patient follow-up. They demonstrate also that the impairment has powerful predictive value with respect to prognosis in patients with type 2 diabetes. Thus, the biochemical evidence of a marked improvement in the balance between fibrinolysis and thrombosis favoring fibrinolysis with the use of insulin sensitizers was compelling.

Results from several studies have shown that increased plasminogen activator inhibitor type-1 (PAI-1) in blood shifts the balance between thrombosis and fibrinolysis favoring thrombosis. Increased PAI-1 portends an increased risk of MI (3) and is manifested by prothrombotic state in patients with polycythemia vera or essential thrombocythemis (4). Increased PAI-1 in blood is a hallmark of type 2 diabetes and is known to be preceded by insulin resistance and compensatory hyperinsulinemia (5). Moreover, insulin increases PAI-1 synthesis and elaboration by liver cells (6), and PAI-1 in blood is increased in normal human subjects rendered hyperinsulinemic (7). Thus, increased PAI-1 in blood is prothrombotic, and the increase seen with type 2 diabetes is driven by insulin resistance and hyperinsulinemia.

Increased expression of PAI-1 in vessel walls, as opposed to blood, is deleterious as well. It can accelerate evolution of atheroma prone to rupture, (i.e., vulnerable plaques). Cell surface activity of plasminogen activators underlies migration of diverse types of cells including vascular smooth muscle cells (VSMC) (8). Their migration from the tunica media into the neointima stabilizes plaques. Accordingly, increased intramural expression of PAI-1 inhibits migration of VSMC’s (9) and exacerbates evolution of vulnerable plaques prone to rupture and precipitate acute coronary syndromes (10-12). It also leads to proliferation of mural cellular components that can contribute to restenosis after PCI (13). In patients with diabetes, PAI-1 in coronary arterial walls is increased (14).

We have shown that treatment with insulin sensitizers lowers PAI-1 expression in patients with insulin resistance associated with obesity and diabetes (15) by lowering concentrations of insulin, free fatty acids, and triglycerides all of which are potent agonist of PAI-1 synthesis. Their use in BARI 2D has led to striking findings (1). PAI-1 antigen, PAI-1 activity and CRP were well-balanced at baseline in insulin providing (IP) and insulin sensitizing (IS) assigned treatment groups, but they increased with IP treatment, and decreased with IS treatment. The divergence was marked, sustained, and highly significant. In addition we found that there was a strong trend towards a reduced incidence of major cardiovascular events among those assigned to the insulin sensitization strategy. Longer follow up will undoubtedly be necessary to determine the magnitude of clinical benefit conferred by an IS strategy since the impact on vessel walls of adverse biological factors and their amelioration is exerted over a lifetime. For example, hypercholesterolemia and hypertension were associated with an increased risk of MI long before treatment of each could be shown to improve survival.

Current Initiatives: We are proceeding to determine the extent to which the propensity to coronary thrombosis on the one hand and the evolution of atherosclerosis can be attenuated by modification of expression of PAI-1 and neutralization of activity of PAI-1 protein. In addition, because PAI-1 has been implicated in acceleration of fibrosis (with excess accumulation of extra-vascular fibrin providing a chemoattractant and scaffolding for deposition of collagen), we are determining whether amelioration of excess PAI-1 in the heart constrains the evolution of heart failure. In addition to procoagulation, acceleration of both atherosclerosis and heart failure are hallmarks of type 2 diabetes, as is over expression of PAI-1. Accordingly, we are delineating the potential benefit of modulating PAI-1 expression in association with diabetes. Studies in these areas are being performed with transgenic mice and rats that over or under express PAI-1 and that can be rendered atherosclerotic and can be induced to develop heart failure by pressure overload aortic banding or secondary to myocardial infarction and can be rendered diabetic with dietary and genetic interventions. They involve also the use of small molecule modulators of PAI-1 activity that have been developed in our ongoing collaboration with industry.

REFERENCES: Including pivotal publications from our laboratory (*)

* 1. Sobel BE, Hardison RM, Genuth S, Brooks MM, McBane RD III, Schneider DJ, Pratley RE, Huber K, Wolk R, Krishnaswami A, Frye RL for the BARI 2D Investigators. Profibrinoytic, anti-thrombotic, and anti-inflammatory effects of an insulin sensitizing strategy in patients in the BARI 2D trial. Circulation 2011; 124:695-703.

* 2. Gogo P, Dauerman HL, Sobel BE. Reperfusion therapies for acute ST segment elevation myocardial infarction. In: Cardiac Intensive Care, 2nd Edition. Edited by Allen Jeremias, M.D. and David Brown, M.D., Elsevier, Philadelphia, 2010, pp. 110-144.

3. Hamsten A, Wiman B, de Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563

4. Cancelas JA, Garcia-Avello A, Garcia-Frade LJ. High plasma level of plasminogen activator inhibitor 1 (PAI-1) in polycythemia vera and essential thrombocythemia are associated with thrombosis. Thromb Res 1994; 75: 513–520

5. Reaven, GM. Role of insulin resistance in human disease. Diabetes. 1988; 37:1595-1607.

6. Nordt TK, Schneider DJ, Sobel BE. Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin: A potential risk factor for vascular disease. Circulation 1994; 89: 321-330

7. Calles-Escandon J, Mirza SA, Sobel BE, Schneider DJ. Induction of hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen activator inhibitor 1 in blood in normal human subjects. Diabetes 1998; 47: 290-293

8. Clowes AW, Clowes MM, Au YP, Reidy MA, Belin D. Smooth muscle cells express urokinase during mitogenesis and tissue-type plasminogen activator during migration in injured rat carotid artery. Circ Res 1990; 67: 61-67

* 9. Schneider, D. J., Hayes, M., Wadsworth, M., Taatjes, H., Rincon, M., Taatjes, D. J., and Sobel, B. E. Attenuation of neointimal vascular smooth muscle cellularity in atheroma by plasminogen activator inhibitor type-1 (PAI-1). J. Histochem. Cytochem 2004; 52: 1091-1099

10. Sobel BE, Taatjes DJ, Schneider DJ. Intramural plasminogen activator inhibitor type-1 and coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2003; 23: 1979-1989.

* 11. Sobel BE. Increased PAI-1 and vasculopathy: A reconcilable paradox. Circulation 1999, 2496-2498

* 12. Sobel BE. Accelerated atherosclerosis, increased intramural PAI-1, and diabetes. Proc Assoc Am Physicians1999; 111:313-318

13. Chen Y, Kelm RJ Jr, Budd RC, Sobel BE, Schneider DJ. Inhibition of apoptosis and caspace-3 in vascular smooth muscle cells by plasminogen activator inhibitor type-1. J. Cell Biochem. 2004; 92:178-188

* 14. Sobel BE, Woodcock-Mitchell J, Schneider DJ, Holt RE, Marutsuka K, Gold H. Increased plasminogen activator inhibitor type-1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: A potential factor predisposing to thrombosis and its persistence. Circulation 1998; 97: 2213-2221

* 15. Kruszynska Y, Yu JG, Sobel BE, Olefsky JM. Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes mellitus and in lean and obese normal subjects. Diabetes. 2000; 49: 633-639

Last modified February 10 2012 04:58 PM