Current Vascular Pharmacology, Vol. 2, No. 2, 2004
Contents
Prostaglandin
J2 Family and the Cardiovascular System Pp. 103-114
Toshiyuki Sasaguri and Yoshikazu Miwa
Endothelial
Dysfunction in Heart Failure: Mechanisms and Therapeutic Approaches Pp.
115-124
Johann Bauersachs
and Andreas Schafer
Prevention
of Endothelial Cell Injury by Activated Protein C: The Molecular Mechanism(s)
and Therapeutic Implications Pp. 125-133
Kenji Okajima
Role
of the Giant Elastic Protein Titin in the Frank-Starling Mechanism of the Heart
Pp. 135-139
Norio Fukuda and
Henk Granzier
The
Role of Vascular Cell Senescence in Atherosclerosis: Antisenescence as a Novel
Therapeutic Strategy for Vascular Aging Pp. 141-148
Tohru Minamino, Hideyuki Miyauchi, Toshihiko Yoshida,
Kaoru Tateno and Issei Komuro
Applications
of Fractal and Non-linear Time Series Analysis to the Study of Short-term Cardiovascular
Control Pp. 149-162
Julian J. Gonzalez and Ernesto Pereda
The
Role of the Chemokines in Myocardial Ischemia and Reperfusion Pp. 163-174
Nikolaos G. Frangogiannis
Passive
Smoking and Coronary Heart Disease Pp. 175-182
Aurelio Leone, Danilo Giannini, Chiara Bellotto and Alberto Balbarini
Gene
Therapy Approaches for the Prevention of Restenosis Pp. 183-189
Christoph W. Kopp and Rainer de Martin
Regulation
of Blood Flow by Prostaglandins Pp. 191-197
R. Boushel, H. Langberg, N. Risum and M. Kjaer
[Back to top] Prostaglandin J2
Family and the Cardiovascular System
Toshiyuki Sasaguri and Yoshikazu Miwa
Prostaglandins (PGs) of the J2 family including PGJ2, D12-PGJ2, and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) are naturally occurring metabolites of PGD2. Among them, 15d-PGJ2 is a powerful ligand for the peroxisome proliferator-activated receptor-g (PPARg). 15d-PGJ2 and synthetic PPARg ligands have been reported to exert several effects on vascular cells, such as anti-proliferative, differentiation-inducing, anti-apoptotic, and anti-inflammatory effects, most of which seem to be atheroprotective, although PPARg-independent mechanisms may be involved. Vascular endothelial cells, intimal smooth muscle cells, and cardiomyocytes express lipocalin-type PGD synthase (L-PGDS) in vivo, which catalyzes the isomeric conversion of PGH2 to PGD2. L-PGDS expression in endothelial cells is stimulated by laminar fluid shear stress. PGD2 and 15d-PGJ2 are detected in the culture medium of endothelial cells exposed to shear stress. Serum and urinary levels of L-PGDS increase in diseases with vascular injuries, such as hypertension and diabetes. Based on these findings, we hypothesize that PGs of the J2 series are physiological substances produced in the vascular wall to protect vascular cells from injurious stimuli and to repress inflammatory reactions. If this hypothesis is correct, PGJ2 family members or other similar substances may provide novel preventive and therapeutic strategies for the treatment of vascular diseases.
[Back to top] Endothelial
Dysfunction in Heart Failure: Mechanisms and Therapeutic Approaches
Johann Bauersachs and Andreas Schafer
Endothelial dysfunction contributes to the development of impaired coronary and systemic perfusion as well as reduced exercise capacity in patients with congestive heart failure (CHF). Thereby endothelial dysfunction is assumed to have a fundamental impact on morbidity and potential mortality in this disease. Reduced bioavailability of nitric oxide (NO) and abundant formation of reactive oxygen species (ROS) within the vascular wall are the key determinants in endothelial dysfunction. The resulting imbalance between NO and ROS mainly results from neurohumoral activation associated with CHF. The excessive activation of the renin-angiotensin-aldosterone and endothelin systems plays a pivotal role. Treatment with ACE inhibitors, angiotensin-, aldosterone-, and endothelin-antagonists has been shown to beneficially modulate endothelial dysfunction in CHF. Furthermore, antioxidants, L-arginine, cofactors of endothelial NO-synthase, and exercise training positively modulate endothelial function.
This article reviews the current knowledge of the pathophysiological events contributing to endothelial dysfunction in CHF as well as several treatment options to reverse those changes.
[Back to top] Prevention of
Endothelial Cell Injury by Activated Protein C: The Molecular Mechanism(s) and
Therapeutic Implications
Kenji Okajima
Activated protein C (APC), a natural anticoagulant, is formed from protein C by the action of thrombin bound to thrombomodulin on the endothelial cell surface. APC regulates the coagulation system by inactivating the activated form of factors V and VIII in the presence of protein S. Tumor necrosis factor-a(TNF-a) plays critical roles in the development of disseminated intravascular coagulation, acute respiratory distress syndrome and shock in sepsis by inducing endothelial cell damage through activation of neutrophils. APC reduces the pulmonary endothelial cell injury and hypotension in rats administered endotoxin (ET) by inhibiting TNF-a production through inhibition of its transcription. Furthermore, APC reduces the ischemia/reperfusion-induced renal injury and the stress-induced gastric mucosal injury in rats. Inhibition by APC of the endothelial cell damage inhibited the decrease in the endothelial production of prostacyclin in vivo. These therapeutic effects could not be attributed to its anticoagulant effects, but to inhibition of TNF-a production. APC inhibits ET-induced TNF-a production in vitro in human monocytes by inhibiting activation of NFkB and AP-1 by inhibiting degradation of IkB and mitogen-activated protein kinase pathways, respectively. Recombinant APC was reported to reduce the mortality of patients with severe sepsis. These observations strongly suggest that APC might be involved not only in regulation of the coagulation system, but in regulation of inflammatory responses by preventing endothelial cell injury. Furthermore, APC reduced the spinal cord injury induced by compression-trauma or ischemia/reperfusion by inhibiting TNF-a production in rats, suggesting that APC may be a potential therapeutic agent for spinal cord injury in which only limited therapeutic measures are currently available.
[Back
to top] Role of the Giant
Elastic Protein Titin in the Frank-Starling Mechanism of the Heart
Norio
Fukuda and Henk Granzier
Increased ventricular volume enhances the systolic performance, a phenomenon known as Frank-Starling’s law of the heart. At its basis is the ability of cardiac muscle to produce increased active force in response to increased muscle length. Although numerous studies have been conducted to elucidate the molecular basis of length-dependent activation, the mechanism remains elusive. The giant protein titin (also known as connectin) is the third filament system in the sarcomere and is responsible for most passive stiffness of striated muscle in the physiological sarcomere length range. The force generated by titin is usually seen as passive and independent of active force generation. Recent findings, however, suggest that titin-based passive force modulates actin-myosin interaction, resulting in greater active force in response to stretch. In this short review, we discuss the molecular mechanisms of length-dependent activation, focusing on the possible role of titin in its regulation.
[Back to top] The Role of Vascular Cell Senescence in Atherosclerosis:
Antisenescence as a Novel Therapeutic Strategy for Vascular Aging
Tohru
Minamino, Hideyuki Miyauchi, Toshihiko Yoshida, Kaoru Tateno and Issei Komuro
Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called “cellular senescence.” It has been reported that many of the changes in senescent vascular cell behavior are consistent with the changes seen in age-related vascular diseases. Recently, senescent vascular cells have been demonstrated in human atherosclerotic lesions but not in non-atherosclerotic lesions. Moreover, these cells express increased levels of proinflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis. One widely discussed hypothesis of senescence is the telomere hypothesis. An increasing body of evidence has established the critical role of the telomere in vascular cell senescence. Introduction of telomere malfunction has been shown to lead to vascular dysfunction that promotes atherogenesis, whereas telomere lengthening extends cell lifespan and protects against vascular dysfunction associated with senescence. Indeed, recent studies have demonstrated that telomere attrition occurs in the blood vessels and is associated with human atherosclerosis. More recent evidence suggests that telomere-independent mechanisms are implicated in vascular cell senescence. Activation of Ras, an important signaling molecule involved in atherogenic stimuli, induces vascular cell senescence and thereby, promotes vascular inflammation in vitro and in vivo. Although a causal link between vascular aging and vascular cell senescence remains elusive, a large body of data is consistent with cellular senescence contributing to age-associated vascular disorders. This review considers the clinical relevance of vascular cell senescence in vivo and discusses the potential of antisenescence therapy for human atherosclerosis.
[Back to top] Applications of Fractal and Non-linear Time Series Analysis
to the Study of Short-term Cardiovascular Control
Julian
J. Gonzalez and Ernesto Pereda
The short-term cardiovascular control system is reviewed from the analysis of the heart rate, respiration and blood pressure beat-to-beat variability signals. The present state of the art concerning fractal and non-linear techniques as applied to the cardiovascular system and the differences between both approaches are highlighted. We present results obtained in mammals from statistics, such as the fractal exponent, the correlation dimension or the maximal Lyapunov exponent and discuss the convenience of these indexes for characterizing the irregularity present in the signals. Finally, the interdependence between the systems involved in the cardiovascular control is addressed. Recent results obtained from interdependence indexes between the cardio, respiratory and vascular signals are discussed and their convenience in physiological studies and clinical applications are stressed.
[Back to top] The Role of the
Chemokines in Myocardial Ischemia and Reperfusion
Nikolaos G. Frangogiannis
Chemokines critically regulate basal and inflammatory leukocyte trafficking and may play a role in angiogenesis. This review summarizes our current understanding of the regulation and potential role of the chemokines in myocardial ischemia and reperfusion. Reperfused myocardial infarction is associated with an inflammatory response leading to leukocyte recruitment, healing and scar formation. Neutrophil chemoattractants, such as the CXC chemokine CXCL8/Interleukin (IL)-8, are upregulated in the infarcted area inducing polymorphonuclear leukocyte infiltration. In addition, mononuclear cell chemoattractants, such as the CC chemokine CCL2/Monocyte Chemoattractant Protein (MCP)-1, are expressed, leading to monocyte and lymphocyte recruitment in the ischemic area. However, chemokines may have additional effects in healing infarcts beyond their leukotactic properties. We have recently described a marked transient induction of the angiostatic CXC chemokine CXCL10/Interferon-g inducible Protein (IP)- 10 in the infarct. Upregulation of angiostatic factors, such as IP-10, in the first few hours following injury may inhibit premature angiogenesis, until the infarct is debrided and appropriate supportive matrix is formed. Suppression of IP-10 synthesis during the healing phase may allow formation of the wound neovessels, a critical process for infarct healing. Chemokine expression is also noted after a single brief ischemic insult in the absence of myocardial infarction, suggesting a potential role for a chemokine-induced inflammatory response in non-infarctive ischemic cardiomyopathy. Unlike cytokines, which have pleiotropic effects, chemokines have more specific cellular targets. Understanding of their role in myocardial infarction may allow us to design specific therapeutic strategies aiming at optimizing cardiac repair and preventing ventricular remodeling.
[Back to top] Passive Smoking and Coronary Heart Disease
Aurelio Leone, Danilo Giannini, Chiara Bellotto and Alberto Balbarini
A large series of clinico-epidemiological studies, meta-analyses and experimental findings have concluded that there is a relationship between coronary heart disease (CHD) and passive smoking either after acute or chronic exposure.
Cigarette smoking is the most important cause of premature death in industrialized countries because it is associated with an increased risk of developing several types of cancer and arterial disease.
In family homes as well as in workplaces, environmental tobacco smoke (ETS) exposure is associated with an increased risk of CHD in exposed non-smokers when compared to un-exposed non-smokers.
Different anatomical structures are damaged by ETS. The endothelium, artery wall and heart are target organs for passive smoking. Therefore, smoking cessation will benefit both smokers and those exposed to ETS.
[Back to top] Gene Therapy Approaches for the Prevention
of Restenosis
Christoph W. Kopp and Rainer de Martin
Experimental gene-therapeutic approaches for the prevention of restenosis after balloon angioplasty are the major source of our insight into pathways operative in the process of vascular renarrowing. We now understand that thrombosis and inflammation are the key mechanisms triggering vascular "healing" in response to injury and know a multitude of potential gene-therapeutic strategies to interfere with appositional thrombus formation, proliferation and migration of vascular smooth muscle cells, lesional recruitment of inflammatory cells or excess deposition of extracellular matrix. Thus far, the major limitation for clinical anti-restenotic gene therapy are concerns about the safety and efficacy of vector systems in use for the local overexpression of transgenes, which in turn is one of the most attractive advantages of gene therapy compared to systemic drug therapy. Here, we review the molecular mechanisms operative in postangioplasty restenosis by highlighting their respective gene therapeutic approaches and the current viral and non-viral vector systems.
[Back to top] Regulation of Blood Flow by Prostaglandins
R. Boushel, H. Langberg, N. Risum and M. Kjaer
Prostaglandins (PGs) belong to the family of prostanoids together with thromboxanes and are produced mainly from arachadonic acid by the enzyme cyclooxygenase. PGs are known to stimulate platelet aggregation, mediate inflammation and edema, play a role in bone metabolism and in biological adaptation of connective tissues e.g. tendon. This review covers the role of PG for mediating tissue blood flow at rest and during increases in metabolic demand such as exercise and reactive hyperaemia. There is strong evidence that PGs contribute to elevate blood flow at rest and during reactive hyperaemia in a variety of tissues. Their role for regulating the large increases in muscle blood flow during exercise is less clear which may be explained by redundant mechanisms. Several interactions are known to exist between specific vasodilator substances, and therefore PGs can act in synergy with other substances and contribute to functional hyperaemia. Furthermore, there is evidence for differential, tissue-specific influences of PGs where their influence on blood flow during exercise may be profound.