Reactive oxygen species (ROS) play important roles in physiological and patho-physiological conditions related to cell growth, differentiation, migration and signaling, extracellular matrix production and degradation, and inflammation in the cardiovascular system. ROS include superoxide anion (^O2), hydrogen peroxide (H2O2), hydroxyl radical (•OH-), and peroxynitrite (ONOO-) as well as other free radicals such as NO.2265 66
Ang II is a critical regulator of ROS generation in many tissues including VSMCs and cardiac, mesangial, and endothelial cells.22 NAD(P)H oxidase is the most important vascular source of ROS. It is composed of five subunits: p22phox, gp91phox (membrane-bound), p47phox, p67phox, and a small G protein Rac1 or Rac2 (cytosolic). In addition to NAD(P)H oxidase, other sources of ROS include xanthine oxidase, uncoupled eNOS, and the mitochondrial respiratory chain.22 ROS generation in response to pressor doses of Ang II plays a major role in the deleterious effects of this peptide. These effects are BP-independent effects of Ang II since similar BP elevation achieved by norepinephrine infusion did not increase vascular •O^ production.67
The pro-growth and hypertensive effects of ROS have also been shown to be mediated by ONOO- production via NO scavenging.68 Many inhibitors of ROS production have been used to elucidate the detrimental role of ROS in hypertension and diabetes: protein nitration, lipid oxidation, and DNA degradation. The inhibitors include superoxide dismutase (SOD) mimetics (Tempol), •O^ scavengers (Tiron), specific inhibitors of NAD(P)H oxidase (apocynin, gp91ds-tat), SOD inhibitors (PEG-SOD), xanthine oxidase inhibitors (allopurinol) or mitochondrial chain inhibitors (thenotrifluoroacetone, carbonyl cyanide-m-chlorophenylhydra-zone and rotenone).69-71 Additionally, ROS interact with second messengers (e.g., intracellular Ca2+), several kinases such as MAPK (ERK, p38, and JNK) and Akt/PKB, and transcription factors (NFkB and AP-1), all leading to the development of vascular inflammation and remodeling.22,72,73
Several studies have demonstrated beneficial vascular inhibitory effects of PPAR activators on ROS production. PPAR-a activators (docosahexaenoic acid, DHA, and fenofibrate) and PPAR-y activators (rosiglitazone or pioglitazone) reduced ROS production in rats infused with Ang II and in endothelin-1-depen-dent hypertensive models such as DOCA-salt hypertensive rats.1674
vascular inflammation and remodeling
One of the major effects of activation of the signaling pathways described is the induction of vascular inflammation found in cardiovascular diseases such as hypertension and in diabetes.75 Of the various systems involved, one of the major mechanisms is the pro-inflammatory effect of Ang II mediated via the ATj receptor.75,76 These effects are mediated by increased expression of adhesion molecules [intercellular adhesion molecule (ICAM)-1, platelet endothelial cell adhesion molecule (PECAM), vascular cell adhesion molecule-1 (VCAM-1), and selectins] and transcription factors (NFkB, AP-1) on monocytes, endothelial cells, and VSMCs.13,77,78
In addition to increased adhesion molecules, Ang II stimulates monocyte chemotactic protein (MCP)-1 synthesis in monocytes/macrophages, endothelial cells, and VSMCs, causing accumulation of inflammatory cells and molecules in the vasculature that ultimately contributes to the development of endothelial dysfunction and vascular remodeling.79 PPAR activators exert potent anti-inflammatory effects. For instance, PPAR-a activation with fenofibrate and gemfibrozil inhibited cytokine production (TNFa, interferon-y interleukin (IL)-6, IL-2, and IL-1p) and adhesion molecule synthesis, whereas eNOS and COX-2 expressions were increased in VSMCs.80-82
These effects were associated with inhibition of expression and activity of transcription factors NFkB and AP-1.83,84 A PPAR-a activator prevented hypertension and vascular remodeling by a reduction in NAD(P)H oxidase activity, VCAM-1 and ICAM-1 expression, in Ang II infused rats.74 PPAR-y also has potent anti-inflammatory properties in addition to its insulin-sensitizing effects. Among beneficial effects reported are reductions in plasminogen activator inhibitor (PAI)-1 in microalbuminuria and in matrix metalloproteinase (MMP)-9 along with increased NO generation.134785 The anti-inflammatory vascular effects of PPAR-y occur through inhibition of NFkB and AP-1, as well as down-regulation of NAD(P)H oxidase subunits.13 86
dual ppar activators
Because of the beneficial cardiovascular effects of PPAR-a and PPAR-y activators such as improvement of lipid metabolism, insulin sensitization, glucose metabolism, vascular remodeling and inflammation, combined activation of these nuclear receptors has been attempted. To date, at least eight dual PPARa/y activators are being evaluated in studies ranging from preclinical to phase III. The activators have been shown to decrease circulating triglyceride concentrations in humans and transgenic human Apo A-I mice.87,88
Dual PPAR-a/y activator effects on glucose metabolism and insulin sensitization are similar to those of PPAR-y activators administered alone.87,88 Two dual PPAR-a/y activators, ragaglitazar and muraglitazar, demonstrated beneficial effects on vascular complications in hypertension and on metabolic abnormalities in diabetes, respectively.89,90 However, muraglitazar administration in type 2 diabetic patients was associated with more death and major adverse cardiovascular events including myocardial infarction, stroke, and transient ischemic attacks, than use of a PPAR-y activator.91
This result dampened interest in these dual PPAR activators, which may not really be superior to agents with single receptor activating capability. Because of these reported deleterious effects, we and others have used a different approach to stimulate both PPAR-a and PPAR-y receptors. We administered concomitantly sub-therapeutic doses of PPAR-a and PPAR-y activators that had beneficial effects when administered in full doses. At these lower doses, a combination of PPAR-a and PPAR-y administration had beneficial effects in a rodent model of Ang II-induced hypertension on vascular function, including improvement of endothelial function, decreased ROS generation, and vascular inflammation. Seber et al. also found that concomitant administration of rosiglitazone and fenofibrate improved the atherogenic dyslipidemic profiles of type II diabetic patients with poor metabolic control.92
Hypertension is highly prevalent and one of the major causes of burden of disease, particularly cardiovascular morbidity and mortality. Diabetes is increasing worldwide, and often is associated with hypertension; it puts hypertensive subjects at the highest cardiovascular risk. Both conditions are associated with vascular injury that serves as the major mechanism for cardiovascular events that lead to myocardial infarction, stroke, amputations, and renal failure.
We have summarized here some of the pathways that participate in growth, inflammation, and oxidative stress that lead to atherosclerosis and vascular remodeling in hypertension and diabetes. PPAR-a and PPAR-y appear to act as countervailing influences on one of the major activators of the pathways that trigger vascular disease, the RAAS. Preclinical and clinical data suggest that PPAR-a and PPAR-y activators may exert important vascular protective effects. Although initial experience with agents endowed with combined PPAR-a and PPAR-y stimulatory effects has been disappointing, mechanistic evidence suggests that agents with these properties that are able to affect the deleterious intracellular signaling pathways described in this chapter may be developed eventually and successfully contribute to reducing the burden of disease generated by hypertension and diabetes.
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