An Emerging Role of Degrading Proteinases in Hypertension and the Metabolic Syndrome: Autodigestion and Receptor Cleavage

Goodwill

American Journal of Physiology-Heart and Circulatory Physiology

et al. 2014

lution of metabolic syndrome is associated with a progressive reduction in skeletal muscle microvessel density, known as rarefaction. Although contributing to impairments to mass transport and exchange, the temporal development of rarefaction and the contributing mechanisms that lead to microvessel loss are both unclear and critical areas for investigation. Although previous work suggests that rarefaction severity in obese Zucker rats (OZR) is predicted by the chronic loss of vascular nitric oxide (NO) bioavailability, we have determined that this hides a biphasic development of rarefaction, with both early and late components. Although the total extent of rarefaction was well predicted by the loss in NO bioavailability, the early pulse of rarefaction developed before a loss of NO bioavailability and was associated with altered venular function (increased leukocyte adhesion/rolling), and early elevation in oxidant stress, TNF-␣ levels, and the vascular production of thromboxane A2 (TxA2). Chronic inhibition of TNF-␣ blunted the severity of rarefaction and also reduced vascular oxidant stress and TxA 2 production. Chronic blockade of the actions of TxA2 also blunted rarefaction, but did not impact oxidant stress or inflammation, suggesting that TxA 2 is a downstream outcome of elevated reactive oxygen species and inflammation. If chronic blockade of TxA 2 is terminated, microvascular rarefaction in OZR skeletal muscle resumes, but at a reduced rate despite low NO bioavailability. These results suggest that therapeutic interventions against inflammation and TxA 2 under conditions where metabolic syndrome severity is moderate or mild may prevent the development of a condition of accelerated microvessel loss with metabolic syndrome. skeletal muscle perfusion; vascular remodeling; vascular reactivity; rodent models of obesity; nitric oxide bioavailability; chronic inflammation EPIDEMIOLOGICAL STUDIES HAVE clearly and consistently demonstrated that both the incidence and prevalence of the metabolic syndrome is continuing to increase in Western society and in most developed economies worldwide (4, 9, 24). Although each of the constituent systemic pathologies (e.g., impaired glycemic control, atherogenic dyslipidemia, hypertension, obesity) have been well documented to increase the risk for development of impaired vascular structure/function and peripheral vascular disease (PVD) (10,11,13,14,16,25,29,45), the significance of this multi-pathology state is that it increases the risk for individuals to develop PVD well beyond that for any single contributing element. Given the impact of PVD on life expectancy, quality of life, depression, and the direct (health care) and indirect (lost productivity) economic costs to society (3, 41, 44), considerable emphasis has been placed on not only the study of PVD and its contributing elements in human subjects but also for the detailed investigation of appropriate animal models of vasculopathy in the metabolic syndrome (1, 49, 51). However, although the existing literature is replet...

supporting

confidence: 56%

Distinct temporal phases of microvascular rarefaction in skeletal muscle of obese Zucker rats

Goodwill

American Journal of Physiology-Heart and Circulatory Physiology

et al. 2014

“…acute insulin resistance (48,49). The ectodomain of this receptor is readily cleaved by proteases, such as MMPs or serine proteases, yielding extracellular (“soluble”) receptor fragments (50). This action renders the receptor unable to signal after insulin binding and therefore contributes to an insulin-resistant state.…”

Section: Protease Activity and Receptor Cleavagementioning

confidence: 99%

“…Other models of acute inflammation provide evidence that receptor degradation by ectodomain cleavage may be a common mechanism for decreased intracellular signaling (50). Since many membrane receptors have potential cleavage sites in their extracellular domains, the phenomenon may play a major role in the multiple organ dysfunction characteristic of shock.…”

Section: Protease Activity and Receptor Cleavagementioning

confidence: 99%

Autodigestion

Altshuler

Kistler

Schmid‐Schönbein

2016

Shock

Self Cite

There is currently no effective treatment for multiorgan failure following shock other than alleviation supportive care. A better understanding of the pathogenesis of these sequelae to shock is required. The intestine plays a central role in multiorgan failure. It was previously suggested that bacteria and their toxins are responsible for the organ failure seen in circulatory shock, but clinical trials in septic patients have not confirmed this hypothesis. Instead, we review here evidence that the digestive enzymes, synthesized in the pancreas and discharged into the small intestine as requirement for normal digestion, may play a role in multi-organ failure. These powerful enzymes are non-specific, highly concentrated and fully activated in the lumen of the intestine. During normal digestion they are compartmentalized in the lumen of the intestine by the mucosal epithelial barrier. However, if this barrier becomes permeable, e.g. in an ischemic state, the digestive enzymes escape into the wall of the intestine. They digest tissues in the mucosa and generate small molecular weight cytotoxic fragments such as unbound free fatty acids. Digestive enzymes may also escape into the systemic circulation and activate other degrading proteases. These proteases have the ability to clip the ectodomain of surface receptors and compromise their function; for example cleaving the insulin receptor causing insulin resistance. The combination of digestive enzymes and cytotoxic fragments leaking into the central circulation causes cell and organ dysfunction, and ultimately may lead to complete organ failure and death. We summarize current evidence suggesting that enteral blockade of digestive enzymes inside the lumen of the intestine may serve to reduce acute cell and organ damage and improve survival in experimental shock.

Antioxidants & Redox Signaling

“…They share common pathogenic mechanisms (80,90), and have causal roles in hypertension through the direct effects of hyperglycaemia, hyperlipidaemia, and hyperinsulinaemia, leading to vascular dysfunction (17,95). Both ER stress and ROS production initiate IR, diabetes, and obesity (18,30,31,73,74), which go on to have direct effects on the peripheral vasculature and result in hypertension.…”

Section: Er Stress and Nox In Ir And Diabetesmentioning

confidence: 99%

Endoplasmic Reticulum Stress and Nox-Mediated Reactive Oxygen Species Signaling in the Peripheral Vasculature: Potential Role in Hypertension

Santos

Nabeebaccus

Shah

et al. 2014

121

Significance: Reactive oxygen species (ROS) are produced during normal endoplasmic reticulum (ER) metabolism. There is accumulating evidence showing that under stress conditions such as ER stress, ROS production is increased via enzymes of the NADPH oxidase (Nox) family, especially via the Nox2 and Nox4 isoforms, which are involved in the regulation of blood pressure. Hypertension is a major contributor to cardiovascular and renal disease, and it has a complex pathophysiology involving the heart, kidney, brain, vessels, and immune system. ER stress activates the unfolded protein response (UPR) signaling pathway that has prosurvival and proapoptotic components. Recent Advances: Here, we summarize the evidence regarding the association of Nox enzymes and ER stress, and its potential contribution in the setting of hypertension, including the role of other conditions that can lead to hypertension (e.g., insulin resistance and diabetes). Critical Issues: A better understanding of this association is currently of great interest, as it will provide further insights into the cellular mechanisms that can drive the ER stress-induced adaptive versus maladaptive pathways linked to hypertension and other cardiovascular conditions. More needs to be learnt about the precise signaling regulation of Nox(es) and ER stress in the cardiovascular system. Future Directions: The development of specific approaches that target individual Nox isoforms and the UPR signaling pathway may be important for the achievement of therapeutic efficacy in hypertension. Antioxid. Redox Signal. 20,[121][122][123][124][125][126][127][128][129][130][131][132][133][134]