By Sayan Chakraborty, Senior Researcher at the Institute of Molecular and Cell Biology, A-STAR, Singapore
In our hectic modern lifestyle, we are constantly subjected to stress of many kinds including the stress experienced by our body from weight-gain. From the physiological perspective, these symptoms are managed by signalling molecules present in the body that control energy expenditure and form new blood vessels (angiogenesis) to cope with increased ‘cellular stress’ levels. These physiological consequences can be precursors to conditions such as type 2 diabetes, one symptom of which is increased angiogenesis.
Proliferative retinopathy, an advanced form of diabetic retinopathy, occurs when abnormal new blood vessels and scar tissue form on the surface of the retina. (Credit: National Eye Institute, National Institutes of Health, USA)
Formation of new blood vessels or expansion of blood circulation allows efficient recycling of nutrients which aids metabolism. The proteins AMP-activated protein kinase (AMPK) and vascular endothelial growth factor (VEGF) are two such ‘stress managers’ activated by stress-activated changes in the metabolism or the blood vessels.
The recent research article published by Heathcote et al., in the Biochemical Journal, sheds light on how VEGF impacts on AMPK activity and provides an interesting insight into the biochemistry of several metabolic diseases. VEGF reportedly influences the addition of phosphate groups to AMPK that subsequently reduces its function. Interestingly, VEGF-induced addition of phosphate groups to AMPK was not mediated by protein kinase-B a protein normally associated with such activities. Instead, VEGF utilized another enzyme, protein kinase-C (PKC), to directly add phosphate groups to AMPK.
AMPK is a well-defined energy sensor in the body and its enzyme activity is turned-on when cellular energy sources are depleted in our body by conditions like low oxygen, low glucose and inadequate blood supply to a part of the body. VEGF, on the other hand, is a primary regulator of angiogenesis in response to growth or cellular stress signals. Even though they are very different in the ways that they operate, occasionally instances emerge when VEGF can influence the action of AMPK. The ability of signalling molecules to influence each other makes this area of biology an exciting area of science. In general, these signalling events are tightly governed by the addition or removal of phosphate groups to proteins which leads to altered metabolic activities. However, in this rapidly evolving field, not much is known as to how the amount of AMPK activity is changed in many medical conditions involving metabolism, such as type 2 diabetes, obesity, cardiovascular disease and cancer development.
The authors of the article found that reducing the functions of PKC by specific drugs abolishes the influence of VEGF on AMPK, thereby increasing AMPK activity. Conversely, increasing PKC levels led to reduced AMPK activity. These interesting findings support the fact that PKC is a bona-fide regulator of AMPK via VEGF.
Primary endothelial cells forming tube-like blood vessels in a culture plate under the influence of VEGF. The relevant question raised in this study is how and whether VEGF can influence the activity of AMPK, which is particularly relevant metabolic disorders.
So how do we make clinical sense of the biochemical evidence illustrated in this study? In obese or diabetic individuals, AMPK activity is reduced by the PKC enzyme. Indeed, PKC activation and the reduction of AMPK activity are correlated with greater insulin resistance, a condition that is a precursor to developing type 2 diabetes. This evidence clearly underlines the importance of AMPK inactivity in obesity and type 2 diabetes. Intuitively, these findings are bound to evoke a lot of exciting thoughts to all researchers in the field. For instance, it is tempting to speculate how the formation of new blood vessels via angiogenesis is altered by VEGF and PKC linked inhibition of AMPK activity.
Since abnormal or excessive blood vessel formation is usually associated with the clinical symptoms of diabetes, it is necessary to test whether this mechanism will serve a prime factor underlining aberrant blood vessel formation in type 2 diabetes.
Will this AMPK-inactivating process be relevant in obesity associated with cancer? If yes, how do we scientifically and clinically prevent the inhibition of AMPK activity as a possible therapy in diabetes, cardiovascular diseases and cancer?
Vascular complications associated with targeted cancer therapies
Even though these observations may serve as the ‘tip of the iceberg’, they clearly convey the impact that VEGF and PKC have on the intricate biology underlining these diseases. However, the major question that remains is ‘how significant is this biochemical observation on disease progression?’ Well, there is one potential way forward: delve deep into the signalling biology intertwining angiogenesis and metabolism and unravel the mysteries we find there.