Pharmacological PTB1B Inhibition Reduces Atherosclerotic Plaque
Researchers here demonstrate a drug that reduces the levels of arterial plaque in a mouse model of atherosclerosis. Removing plaque is the best way to address this condition, next to preventing it from occurring in the first place. The SENS view on how to go about this is to find bacterial enzymes capable of digesting the problem compounds that cause inflammation and spur generation of atherosclerotic plaque. Those enzymes can be used as a starting point for the development of drug candidates. Other approaches include engineering macrophages - the cells that try to clear plaque compounds and die, making the problem worse - to be more resilient and capable, or selectively destroying dysfunctional macrophages that linger to produce inflammation that makes the plaque site more damaging to surrounding tissues.
The alternative approach illustrated here is to reduce the pace at which new cells arrive at the plaque site only to be overwhelmed and die, expanding the plaque with their debris. The researchers show that PTB1B inhibition both reduces inflammation and interferes in the signaling that recruits more cells to attempt to deal with the plaques. This appears to dial back the feedback loop of inflammation, cell arrival, and cell death sufficiently to allow natural mechanisms to reduce existing plaques, reversing the progression of atherosclerosis.
Many conditions that contribute to cardiovascular diseases (CVDs) are due to narrowing and hardening of the blood vessels through a process known as atherosclerosis, arising due to lipid accumulation which, over time, develops into plaques. Subsequently, these atherosclerotic plaques can lead to ischaemic injury by a number of mechanisms such as complete occlusion of the blood vessel or alternatively, the plaque may become unstable and rupture resulting in thrombosis. This process may be exacerbated by risk factors encompassing genetic aspects, lifestyle choices such as smoking, excessive drinking, physical inactivity and obesity or conditions such as diabetes.
Indeed, in both type 1 and type 2 diabetic patients, a high proportion of mortality is associated with CVD, where defective insulin signalling leads to endothelial dysfunction and accelerated atherosclerosis. The mechanism contributing to this pathology is somewhat unclear; however, it has been suggested that insulin resistance (IR) and hyperglycaemia results in intracellular metabolic changes leading to oxidative stress and chronic low-grade inflammation. Therefore, targeting components that inhibit IR signalling could prove to be an effective therapeutic.
Protein tyrosine phosphatase (PTP)1B (PTP1B) has been identified as the major negative regulator of the IR itself. In mice, whole body PTP1B-/- studies established PTP1B as a major regulator of insulin sensitivity and body mass, via inhibition of insulin and leptin signalling respectively. Our recent data suggested that hepatic-specific deletion of PTP1B, in addition to improving glucose and lipid homoeostasis and increasing insulin sensitivity, was protective against endothelial dysfunction in response to high fat diet (HFD). This was also associated with decreased hepatic inflammation in these mice. Since atherosclerosis is regarded as a chronic low level inflammatory disease, we hypothesized that targeting PTP1B activity using a PTP1B-specific inhibitor trodusquemine, could prove effective in prevention and possibly reversal of atherosclerotic plaque formation.
We demonstrate here, using the LDLR-/- mouse model of atherosclerosis, that pharmacological PTP1B systemic inhibition leads to protection against and reversal of atherosclerosis development, suggesting beneficial effects of PTP1B inhibition for the treatment of CVDs and reduction in CVD risk. We present evidence that, in addition to its improvement in glucose homeostasis and adiposity, PTP1B inhibition results in activation of aortic Akt and AMPKα1, that is independent of the effects on the IR itself. Most importantly, for the first time, we demonstrate that inhibition of PTP1B results in a decrease in circulating serum cholesterol and triglyceride levels and protection against atherosclerotic plaque formation.
Atherosclerosis is now widely regarded as a chronic, low-grade inflammatory condition characterized by an increased pro-inflammatory environment and decreased anti-inflammation, pro-resolutionary signalling. Thus, a vicious cycle ensues and a failure of the tissue to return to homeostasis. Therefore, we investigated the expression of genes important in the inflammatory response including MCP-1, ICAM-1 and VCAM-1. MCP-1 is responsible for recruiting monocytes to the aortic tissue whereas both ICAM-1 and VCAM-1 enable their transmigration. Although there were no changes in the expression of aortic ICAM-1 or VCAM-1, those animals treated with a single injection of trodusquemine exhibited attenuated aortic MCP-1 expression levels. Hence, suggesting less monocyte recruitment and a reduced inflammatory environment which could contribute to the reduction in plaque development.