Farhad Amiri Karim Benkirane and Ernesto L Schiffrin

contents

Introduction 196

MAPK Signaling in Vascular Remodeling 198

ERK1 and ERK2 Signaling, Effects of PPAR-y, and Vascular Remodeling ..199

p38 Signaling in Vascular Remodeling 200

Role of JNK Signaling in Vascular Remodeling 201

PI3K Signaling Pathway and Vascular Remodeling 201

Role of Akt/PKB Signaling Pathway in Vascular Remodeling 202

ROS and Vascular Remodeling 202

Vascular Inflammation and Remodeling 203

Dual PPAR Activators 204

Conclusion 204

References 205

introduction

In both hypertension and diabetes mellitus significant changes that occur in the vasculature affect both large and small arteries and lead to cardiovascular events such as myocardial infarction, stroke, peripheral vascular disease, and compromise of renal function. In addition, diabetes also involves microvascular disease in different vascular beds including the retina and the kidney that contribute to the morbidity, and in the case of the kidney, the mortality associated with diabetes.

The degree and importance of vascular disease and its contribution to mortality in diabetes are such that diabetes has been called a vascular disease although its origin is undoubtedly metabolic. Moreover, hypertension and diabetes are often associated: approximately 20% of hypertensives may become diabetic and 80 to 90% of type 2 diabetic patients develop hypertension. Description of the nature of vascular disease in hypertension and diabetes, its mechanisms, and therapeutic targets, potential and already demonstrated, become accordingly extremely important. Some of these will be dealt with in this chapter, particularly in relation to signaling pathways and putative vascular protective effects of activation of peroxisome proliferator-activated receptors (PPARs).

Vascular injuries in large arteries in hypertension and diabetes differ mainly in intensity and are much more severe in diabetes. In large arteries, injuries of both the intima with development of atherosclerosis and of the media with arteriosclerosis occur. The description of the atherosclerotic process is beyond the scope of this chapter. It is sufficient to say that the severity of atherosclerosis in diabetes is such that it affects the peripheral circulation, leading to amputation of lower limbs, and also affects the coronary circulation where diabetes is considered a "coronary equivalent."1

In small (resistance) arteries that measure 150 to 300 pm in lumen diameter, hypertension is associated with remodeling changes that lead to increased peripheral resistance — the hallmark of essential hypertension. The remodeling of small arteries in hypertension is eutrophic — reduced outer and lumen diameters with increased media-to-lumen ratio and no significant increase in cross-sectional area of the media.2-4 Associated with the structure changes are deposition in the media of extracellular matrix components such as collagen and fibronectin5 and dysfunction of the endothelium.6 Diabetes, on the other hand, involves hypertrophic remodeling in which the media-to-lumen ratio is also increased along with an increased media cross-section, achieving true media hypertrophy.7,8 Deposition of collagen is less important. More frequently than in hypertension, endothelial dysfunction is the norm.8,9

In the United Kingdom Prospective Diabetes Study (UKPDS), tight blood pressure (BP) controls in hypertensive patients with type 2 diabetes reduced the risk of macrovascular disease, stroke, and deaths related to diabetes.10 Most hypertension randomized clinical trials failed to show beneficial effects on cardiac ischemia expected from population studies. Thus, blood pressure lowering may not be enough to normalize remodeled arteries in hypertensive or diabetic subjects. In hypertensive patients, the extent and consequences of tissue ischemia

(in the heart, kidney, or brain) are influenced by small vessel disease.3 The intermediate coronary lesions that are frequent in hypertensive and diabetic subjects will produce changes in flow if small artery remodeling is present.

The renin-angiotensin-aldosterone system (RAAS) plays a critical role in the initiation and progression of cardiovascular disease.11 The RAAS contributes to vascular remodeling of small arteries through different pathways. Angiotensin II (Ang II) can indirectly promote vascular remodeling through hemodynamic effects or directly activate myriad intracellular signaling pathways such as mito-gen-activated protein kinase (MAPK), phosphoinositide-3 kinase (PI3K), Janus kinase/signal transducers and activators of transcription (JAK/STAT), and reactive oxygen species (ROS) through AT1 receptors. Ang II may also transactivate growth factor receptors such as epidermal growth factor receptor (EGFR).12 These pathways in turn initiate cascades in which different key proteins are stimulated, including nuclear factors that are responsible for cardiovascular gene transcription. The involvement of RAAS in hypertension and diabetes-related complications has been clarified through the use of a variety of RAAS inhibitors including but not limited to angiotensin converting enzyme (ACE) inhibitors, Ang receptor blockers (ARB), and aldosterone receptor antagonists.3

Insulin-sensitizing thiazolidinediones (TZDs) or glitazones may exert protective cardiovascular properties in part through the prevention of vascular remod-eling.13 For instance, TZDs such as pioglitazone and rosiglitazone reduced blood pressure in several hypertensive rodent models including Ang II-infused rats, stroke-prone spontaneously hypertensive rats (SHRSP), and deoxycorticosterone acetate (DOCA)-salt hypertensive rats.14-16 Blood pressure lowering was accompanied by prevention of vascular remodeling and endothelial dysfunction and down-regulation of inflammatory mediators in these rodent models. Although the hypotensive effects of TZDs observed in rodents were not observed in humans, other beneficial effects such as prevention of vascular remodeling, improvement of endothelial function,1718 and down-regulation of inflammatory markers19 have been reported.

TZDs mediate their effects through binding of PPAR-y, a ligand-activated transcription factor belonging to the nuclear receptor superfamily. Forming a dimer with RXR and associated to co-activators and co-repressors, PPAR-y binds to DNA PPAR response elements (PPREs) and regulates many genes implicated in carbohydrate metabolism, inflammation and thrombosis, endothelial function and cell growth.20 Other PPAR isoforms include PPAR-a, which is activated by fatty acids and by lipid lowering fibrates and predominantly expressed in tissues exhibiting high fatty acid catabolism such as liver, heart, kidney, and skeletal muscle. Another isoform is PPAR-p/5, which is expressed ubiquitously and is involved in fatty acid oxidation.21

The major beneficial effects of TZDs have been attributed to their actions on several protein kinases such has MAPK, PI3K, and ROS-generating enzymes, all of which have been implicated in vascular remodeling in hypertension.1422

mapk signaling in vascular remodeling

MAPK signaling has been largely studied for processes such as hyperplasia and hypertrophy associated with cell growth, and pro-inflammatory pathways, all of which are found in hypertensive and diabetic vascular remodeling. These serine/threonine kinases are subdivided into six subfamilies: extracellular signalregulated kinases 1 and 2 (ERK1/2), p38, c-jun N-terminal protein kinase (JNK), ERK3, ERK5, and ERK6.23 Due to elaborate cross-talk among these kinases, we will focus only on ERK1/2, p38 and JNK proteins because they are the most commonly studied (Figure 12.1).

Activation of MAPK is associated with cell growth, programmed cell death (apoptosis), cell transformation and differentiation, and cell contractility. ERK1/2 proteins can be activated by different growth factors whereas p38 and JNK proteins are generally activated by cytokines and cellular stress.23 Ang II is a potent stimulator of MAPK pathways through various upstream second messenger systems.12,24,25

MAPK activation requires phosphorylation of threonine and tyrosine residues by other kinases such as mixed lineage kinases (MLKs), MAPK kinase, or mitogen extracellular-regulated kinase (MEK). MEKs are activated by serine/threonine MEK kinases (Raf-1, A-Raf and B-Raf), which are in turn activated by small protein G (Ras family) and other kinases.26,27 Raf phosphorylation is influenced by different kinases such as c-Src, protein kinase C (PKC), protein kinase B (PKB), and p21 (rac/Cdc42)-activated protein kinase (PAK).26

Stress, cytokines, growth factors

Growth factors 1

Stress, cytokines, growth factors

Growth factors 1

Stimulus

Diabetes Sustenance

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