Ultimately results in the production of cholesterol and ster

Ultimately results in the production of cholesterol and sterol components. The ubiquitin-proteasome system responsible for removal of misfolded or damaged proteins �C is also implicated in the onset of such metabolic side effects. For example, the PI Ritonavir 152918-18-8 chemical information attenuates chymotrypsin- and trypsin-like activities of the 20S UPS subunit in hepatocytes. As a result, degradation of apolipoprotein B was diminished thus providing a potential mechanism for PI-induced hyperlipidemia. Furthermore, SREBPs are ubiquitinated and degraded by the UPS raising the possibility that an inhibition of this system may also contribute to development of dyslipidemia in HIV-infected individuals treated with PIs. Together this may establish a pro-atherogenic profile and increase the risk for the onset of CVD. Despite such progress, the underlying molecular mechanisms responsible for HAART-induced cardio-metabolic side effects are poorly understood, and little is known about the earliest events driving this process. Whether these molecular alterations occur as a direct result of PI treatment or through the activation of additional pathways throughout the body at a later stage remain elusive. For the current study, we therefore hypothesized that PI treatment enhances myocardial oxidative stress and concomitantly inhibits the UPS, having a knock-on effect on important downstream 1381289-58-2 manufacturer regulators such as gap junctions and ion channels essential in cardiac physiology. We also evaluated several nonoxidative glucose metabolic circuits i.e. the polyol pathway, hexosamine biosynthetic pathway, advanced glycation end products, and PKC activation since previous work found its activation can elicit the onset of cardio-metabolic complications. Since our previous ex vivo rat heart study implicated altered calcium homeostasis in PI-mediated cardiac dysfunction, we further investigated calcium signaling and mitochondrial energetic regulators in an established rat model of chronic PI drug delivery. These data may explain and suggest an association between molecular changes and depressed cardiac contractile function. Although HAART markedly improves the quality of life and prognosis of HIV-infected individuals, it also elicits cardiometabolic side effects in the long-term. Since molecular mechan