Slug, a Cancer-Related Transcription Factor, is Involved in Vascular Smooth Muscle Cell Transdifferentiation Induced by Platelet-Derived Growth Factor-BB During Atherosclerosis.

Background Heart attacks and stroke often result from occlusive thrombi following the rupture of vulnerable atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) play a pivotal role in plaque vulnerability because of their switch towards a proinflammatory/macrophage-like phenotype when in the context of atherosclerosis. The prometastatic transcription factor Slug/Snail2 is a critical regulator of cell phenotypic transition.

Novel short isoforms of adenylyl cyclase as negative regulators of cAMP production.

Here, we cloned a new family of four adenylyl cyclase (AC) splice variants from interleukin-1β (IL-1β)-transdifferentiated vascular smooth muscle cells (VSMCs) encoding short forms of AC8 that we have named "AC8E-H". Using biosensor imaging and biochemical approaches, we showed that AC8E-H isoforms have no cyclase activity and act as dominant-negative regulators by forming heterodimers with other full-length ACs, impeding the traffic of functional units towards the plasma membrane. The existence of these dominant-negative isoforms may account for an unsuspected additional degree of cAMP signaling regulation.

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In response to various types of vascular stress, the smooth muscle cells of the vessel wall (VSMCs) change phenotype and acquire the capacity to react to abnormal signals. This phenomenon favors the involvement of these cells in the development of major vascular diseases, such as atherosclerosis, and some complications of angioplasty, such as restenosis. The cyclic adenosine monophosphate (cAMP) pathway plays a key role in the integration of stimuli from the immediate environment and in the development of cellular responses.

The Notch pathway attenuates interleukin 1β (IL1β)-mediated induction of adenylyl cyclase 8 (AC8) expression during vascular smooth muscle cell (VSMC) trans-differentiation.

Vascular smooth muscle cell (VSMC) trans-differentiation, or their switch from a contractile/quiescent to a secretory/inflammatory/migratory state, is known to play an important role in pathological vascular remodeling including atherosclerosis and postangioplasty restenosis. Several reports have established the Notch pathway as tightly regulating VSMC response to various stress factors through growth, migration, apoptosis, and de-differentiation. More recently, we showed that alterations of the Notch pathway also govern VSMC acquisition of the inflammatory state, one of the major events accelerating atherosclerosis.

Wild-type amyloid beta 1-40 peptide induces vascular smooth muscle cell death independently from matrix metalloprotease activity.

Cerebral amyloid angiopathy (CAA) is an important cause of intracerebral hemorrhages in the elderly, characterized by amyloid-β (Aβ) peptide accumulating in central nervous system blood vessels. Within the vessel walls, Aβ-peptide deposits [composed mainly of wild-type (WT) Aβ(1-40) peptide in sporadic forms] induce impaired adhesion of vascular smooth muscle cells (VSMCs) to the extracellular matrix (ECM) associated with their degeneration. This process often results in a loss of blood vessel wall integrity and ultimately translates into cerebral ischemia and microhemorrhages, both clinical features of CAA.

Retinoids upregulate phosphoenolpyruvate carboxykinase and glyceroneogenesis in human and rodent adipocytes.

Glyceroneogenesis is an important metabolic pathway for fatty acid reesterification in adipose tissue, thereby reducing fatty acid release. Glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), which is the key enzyme in this pathway, are both regulated by a series of hormones and nutrients, among which all-trans retinoic acid (all-trans RA) is a transcriptional inducer of the PEPCK-C gene (Pck1). All-trans RA binds to the retinoic acid receptor (RAR) and activates it, whereas its stereoisomer 9-cis retinoic acid (9-cis RA) is a ligand for the 9-cis RA receptor (RXR).

The benefit of docosahexanoic acid on the migration of vascular smooth muscle cells is partially dependent on Notch regulation of MMP-2/-9.

The Notch pathway is involved in the regulation of the migratory/proliferative phenotype acquired by vascular smooth muscle cells (VSMCs) in the pro-inflammatory context of vascular diseases. Here, we investigated whether docosahexaenoic acid (DHA), a polyunsaturated, omega-3 fatty acid, could reduce fibrinolytic/matrix-metalloproteinase (MMP) activity and whether this reduction occurs through the modulation of Notch signaling. Rat VSMCs were transdifferentiated with interleukin-1beta and then treated with DHA.

Pathophysiology of the HIV-Associated Lipodystrophy Syndrome.

The widespread use of highly active antiretroviral therapy (HAART) has radically transformed the prognosis of HIV-infected patients in the developed countries. Unfortunately, a serious metabolic syndrome combining peripheral lipoatrohy, central adiposity, insulin resistance, and dyslipidemia has arisen in these individuals. The etiology of this heterogeneous syndrome named lipodystrophy syndrome (LDS) is multifactorial, but adipose tissue is very likely a key factor that contributes to several clinical or metabolic aspects of the syndrome.

Notch3 and IL-1beta exert opposing effects on a vascular smooth muscle cell inflammatory pathway in which NF-kappaB drives crosstalk.

Atherogenesis begins with the transfer of monocytes from the lumen to the intimal layer of arteries. The paracrine activity acquired by these monocytes shifts vascular smooth muscle cells from a contractile-quiescent to a secretory-proliferative phenotype, allowing them to survive and migrate in the intima. Transformed and relocated, they also start to produce and/or secrete inflammatory enzymes, converting them into inflammatory cells.

PGE2 amplifies the effects of IL-1beta on vascular smooth muscle cell de-differentiation: a consequence of the versatility of PGE2 receptors 3 due to the emerging expression of adenylyl cyclase 8.

Transition of vascular smooth muscle cells from a contractile/quiescent to a secretory/proliferative phenotype is one of the critical steps in atherosclerosis and is instigated by pro-inflammatory cytokines released from macrophages that have infiltrated into the vascular wall. In most inflammatory diseases, cell activation induced by these compounds leads to a massive production of type E2 prostaglandin (PGE2) which often takes over and even potentiates the pro-inflammatory cytokine-related effects. To evaluate PGE2 incidence on atheroma plaque development, we investigated whether and how this compound could enhance the dedifferentiation of smooth muscle cells initially induced by interleukin-1beta (IL-1beta).

In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes.

A serious metabolic syndrome combining insulin-resistance, dyslipidemia, central adiposity, and peripheral lipoatrophy has arisen in HIV-infected patients receiving highly active antiretroviral therapy. The aim of this work was to examine the effects of the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz on adipocyte differentiation and metabolism. When induced to differentiate in the presence of efavirenz (5-50 microm), 3T3-F442A preadipocytes failed to accumulate cytoplasmic triacylglycerol droplets.

Evidence for selective induction of phosphoenolpyruvate carboxykinase gene expression by unsaturated and nonmetabolized fatty acids in adipocytes.

Polyunsaturated fatty acids (PUFAs) and 3-thia fatty acids are hypolipidemic and decrease insulin resistance in Type II diabetic animals. To exert such an action, these FAs could decrease adipose tissue lipolysis or increase esterification. Glyceroneogenesis is an important metabolic pathway in adipocytes for re-esterification of FAs originating from lipolysis and in hepatocytes for triacylglycerol synthesis during fasting.