Cardiovascular & Hematological Disorders - Drug Targets

ISSN: 1871-529X

Contents

A Stress Repair Mechanism That Maintains Vertebrate Structure During Stress, 2010, 10, 111-137
Lewis S. Coleman
[Abstract] [Full Text Article]


A Systems Biology Consideration of the Vasculopathy of Sickle Cell Anemia: The Need for Multi-Modality Chemo-Prophylaxis, 2009, 9, 271-292
Robert P. Hebbel, Greg M. Vercellotti and Karl A. Nath
[Abstract] [Full Text Article]


HMG-CoA Reductase Inhibitors: Effects on Chronic Subacute Inflammation and Onset of Atherosclerosis Induced by Dietary Cholesterol, 2005, 5, 441-453
R. Kleemann and T. Kooistra
[Abstract] [Full Text Article]



Abstracts


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A Stress Repair Mechanism That Maintains Vertebrate Structure During Stress
Lewis S. Coleman

[Full Text Article]

Based on Capillary Gate Theory and Tissue Repair Theory, this paper describes the “Stress Repair Mechanism” (SRM) that maintains and repairs vertebrate tissues. It accounts for most of the mysterious manifestations of allostasis thatremain unexplained by Hypothalamic-Pituitary-Axis (HPA) hormones and thereby enables the Universal Theory of Medicine predicted by Hans Selye. SRM activity explains hemodynamic physiology, capillary hemostasis, infarction, Korotkoff sounds, blood pressure, hypertension, diabetes, allostasis, allostatic load, anesthesia, analgesia, atherosclerosis, apoptosis, malignancy, eclampsia, sepsis, Multi-System Organ Failure (MSOF), the surgical stress syndrome, the fight or flight response, and numerous other manifestations of physiology and pathology. SRM function comprises the autonomic nervous system, the vascular endothelium, and the dynamic enzymatic interaction of blood-borne hepatic Factors VII, VIIIC, IX and X that produces thrombin, soluble fibrin and insoluble fibrin, whose combined effects account for all SRM manifestations. The vascular endothelium is a diaphanous neuroendocrine organ that lines all blood vessels and is the sole constituent of capillary walls. It secretes tissue factor into extravascular tissues, and insulates those tissues from the hepatic enzymes, so that tissue disruption exposes tissue factor to the enzymatic interaction and activates tissue repair. The vascular endothelium also releases nitric oxide and von Willebrand Factor into blood in accord with autonomic balance to regulate the enzymatic interaction to govern tissue perfusion and organ function. Therefore, continuously fluctuating combinations of nervous stimuli that affect autonomic balance and forces that disrupt tissues determine SRM activity.


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A Systems Biology Consideration of the Vasculopathy of Sickle Cell Anemia: The Need for Multi-Modality Chemo-Prophylaxis
Robert P. Hebbel, Greg M. Vercellotti and Karl A. Nath

[Full Text Article]

Much of the morbidity and mortality of sickle cell anemia is accounted for by a chronic vasculopathy syndrome. There is currently no identified therapy, interventional or prophylactic, for this problem. For two reasons, development of an effective therapeutic approach will require a systems biology level perspective on the vascular pathobiology of sickle disease. In the first place, multiple biological processes contribute to the pathogenesis of vasculopathy: red cell sickling, inflammation and adhesion biology, coagulation activation, stasis, deficient bioavailability and excessive consumption of NO, excessive oxidation, and reperfusion injury physiology. The probable hierarchy of involvement of these disparate sub-biologies places inflammation caused by reperfusion injury physiology as the likely, proximate, linking pathophysiological factor. In the second place, most of these sub-biologies overlap with each other and, in any case, have multiple points of potential interaction and transactivation. Consequently, an approach modeled upon chemotherapy for cancer is needed. This would be a truly multi-modality approach that hopefully could be achieved via employment of relatively few drugs. It is proposed here that the specific combination of a statin with suberoylanilide hydroxamic acid would provide a suitable, broad, multi-modality approach to chemo-prophylaxis for sickle vasculopathy.


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HMG-CoA Reductase Inhibitors: Effects on Chronic Subacute Inflammation and Onset of Atherosclerosis Induced by Dietary Cholesterol
R. Kleemann and T. Kooistra

[Full Text Article]

Besides classical risk factors such as hypercholesterolemia and hypertension, chronic subacute inflammation has recently been recognized as an important force driving the development of atherosclerosis, the most common underlying cause of myocardial infarction and stroke. There is compelling evidence that a disturbance of cholesterol homeostasis contributes to the development of a chronic inflammatory state and that inhibitors of HMG-CoA reductase (statins) may dampen inappropriate inflammatory responses. We review the evidence and suggest mechanisms by which dietary cholesterol can induce an atherogenic inflammatory response in liver and vessel wall, with particular emphasis on the time course of this inflammatory response during atherogenesis and the interplay between these tissues. We discuss how statins interfere in this process, and whether they may reduce chronic subacute inflammation via a) their cholesterol-lowering effect, and/or b) their cholesterol-independent (pleiotropic) vasculoprotective activities. Recent studies performed in (humanized) animal models allow us to distinguish the lipid-lowering—dependent from the lipid-lowering—independent functions of statins. Using these data, we discuss the degree to which the lipid-lowering—dependent and lipi lowering—independent effects of statins contribute to a reduction of inflammation, allowing estimation of the relevance of pleiotropic statin effects for the human situation.