Gle

Rosiglitazone

ERK1/2

Cell growth and vascular remodeling independent of ERK1/2

Transcription factors

Cell growth and vascular remodeling

FIGURE 12.2 Angiotensin (Ang) II effects on extracellular-regulated kinase (ERK) 1 and 2 activation in resistance and conduit arteries.

signaling in aortic VSMCs. These data collectively demonstrate the countervailing effects of PPAR activators on MAPK signaling pathways implicated in cell growth and migration induced by vasoactive agents such as Ang II.

p38 SIGNALING IN VASCULAR REMODELING

p38 MAPK comprises six isoforms (p38a1 and a2, p38p1 and p2, p388, and p38y): the a and p isoforms are ubiquitous; the 8 isoform is expressed mainly in kidneys, lungs, and pancreas; and the y isoform is highly expressed in skeletal muscle.39 p38 MAPK can be activated by a variety of stimuli including cytokines, growth factors, osmotic shock, and different stressors. p38 MAPK has been implicated in several pathophysiological conditions such as atherosclerosis, hypertensive vascular remodeling, and ischemic cardiomyopathy.26

Ang II can stimulate vascular p38 MAPK, affecting inflammatory responses, apoptosis, cell growth inhibition, and contractility. Inhibition of p38 MAPK reduced these effects in aortic but not mesenteric VSMCs.40-42 p38 MAPK crosstalks with other members of the MAPK family (including ERK1/2, MEK3, and MEK6; see Figure 12.1) and other signaling molecules (e.g., heat shock protein 27), which is important in cytoskeletal reorganization implicated in cell migration and vascular remodeling.26,39 p38 MAPK is also regulated by PPAR-a and one of its co-activators, PGC-1, suggesting a regulatory role for p38 MAPK in PPAR-a-mediated lipid metabolism.27 However, p38 MAPK does not seem to participate in PPAR-y regulation, as inhibition of p38 MAPK failed to modulate PPAR-y-induced AT1 gene transcription.43

This further demonstrates differential effects of different MAPKs on the RAAS. Since p38 MAPK may also induce VSMC apoptosis, PPAR-a activators such as ra-3 fatty acids (e.g., docosahexaenoic acid) may stimulate VSMC apoptosis via a p38/PPAR-a-dependent manner.44 As with ERK1/2, endogenous (retinoic acid) and synthetic PPAR ligands (various TZDs such as ciglitazone, troglitazone, and rosiglitazone) modulate p38 MAPK activity.384546 However, both ciglitazone and 15d-PGJ2 are potent stimulators of p38 MAPK activity in rat astrocytes but not in mesangial cells.4547 These data demonstrate that PPARs have the ability to directly and indirectly regulate MAPKs in a tissue-dependent manner.

role of jnk signaling in vascular remodeling

The third member of the MAPK family that we will address is c-Jun N-terminal kinase (JNK) which comprises JNK1, JNK2, and JNK3. JNKs can be stimulated by several cytokines, growth factors, stressors, and vasoactive agents (Ang II and endothelin-1).26 Contrary to the pro-stimulatory effects of Ang II on cell growth via ERK1/2, JNK activation induced apoptosis and cell cycle inhibition.

Once activated, JNKs activate transcription factors such as c-Jun, c-Myc, PPAR-a, and PPAR-y.27,48 Ang II-induced JNK activation is dependent upon other factors such Ca2+ mobilization and PKC-^ activation, but is independent of c-Src activation.49 JNK also seems to be activated in a cell-specific manner. In cardiac fibroblasts, Ang II stimulated JNK via PKC-independent proline-rich tyrosine kinase 2/Rac1, whereas in VSMCs this occurs through PAK, PKC, and Ca2+.50

Contrary to the other MAPK proteins, the cellular effects of PPARs on the JNK pathway remain to be fully elucidated in VSMCs. PPAR-y activation may induce JNK signaling involved in apoptosis. Taken together, all MAPK pathways are involved in molecular mechanisms that ultimately lead to development and maintenance of cardiovascular dysfunction such as the vascular remodeling observed in hypertension and diabetes.

pi3k signaling pathway and vascular remodeling

The PI3K pathway is implicated in cardiovascular events such as cardiac and vascular remodeling, heart failure, and endothelial dysfunction.51,52 The PI3K family is composed of 3'-OH inositol phosphorylating enzymes and includes members of three classes divided according to their molecular structures, activation mechanisms, and substrate specificities. Class I (A and B) is composed of heterodimeric regulatory and catalytic subunits while class II proteins are composed of single catalytic subunits (PI3K-C2a, PI3K-C2p, or PI3K-C2y).53 Class IA has three catalytic (p110a, p, and 8) and three regulatory subunits (p85a, p85p, and p55y) expressed mostly in the heart and blood vessels. However, class IB contains only one protein kinase composed of a p110y catalytic subunit and a p101 regulatory subunit, expressed predominantly in cardiomyocytes, fibro-blasts, endothelial cells, and VSMCs.53

The importance of PI3K in Ang II-induced cardiac hypertrophy and VSMC proliferation has been established with the use of specific reversible (LY294002)

and irreversible (wortmannin) inhibitors.51 PI3K regulates cell growth and survival, cytoskeletal reorganization, ROS production, and glucose transport among other functions and plays a role in the progression of cardiac hypertrophy and dysfunction and in vascular remodeling.52-54 PI3K is regulated by other kinases such as Rho kinase, which may contribute to endothelial dysfunction.55 PI3K participates in endothelial nitric oxide synthase (eNOS) activation and thus in NO generation and vasodilation.56

Ang Il-stimulated ERK1/2 activity was blunted by the PI3K inhibitor LY-294009 in mesenteric artery VSMCs from hypertensive rats but not normotensive rats, which may imply cross-talk between PI3K and ERK1/2 pathways.29 PPAR-y regulates PI3K activity. Rosiglitazone induced PI3K/p85a expression and activity in adipocytes and in conduit and resistance arteries, but not in skeletal mus-cle.1457 58 These data suggest that altered PI3K activity and expression may occur at the initiation and during the maintenance phase of hypertensive vascular disease.

ROLE OF Akt/PKB SIGNALING PATHWAY IN VASCULAR REMODELING

A key protein within the PI3K signaling pathway is Akt, also known as protein kinase B (PKB). In mammals, three Akt/PKB isoforms (Aktl/PKBa, Akt2/PKBp, and Akt3/PKBy) are highly expressed in cardiac, vascular, and endothelial cells.53 They are regulated by PI3K, SH2-containing inositol phosphatase (SHIP2) and phosphoinositide-dependent kinase (PDK)-1 and -2.59 Once activated, Akt/PKB modulates cell survival, growth, migration, and glucose metabolism.60-63 Synthetic and endogenous PPAR ligands inhibit Akt/PKB in blood vessels and other tissues, possibly through the inhibition of eukaryotic initiation factor-4E-binding protein (4E-BP)-1, a protein implicated in cellular growth.14,64

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