One of the key features of cardiovascular complications, such as hypertension or diabetes, is that they often appear at the same time in the same individual together with other forms of co-morbidities. While clinically a recognized phenomenon, no molecular mechanism for such co-morbidities has received universal acceptance. We propose a new hypothesis that provides a molecular basis for co-morbidities in hypertension due to unchecked proteolytic activity and receptor destruction. Testing of the hypothesis in the spontaneously hypertensive rat reveals an unchecked matrix metalloproteinase and serine protease activity in plasma and on several cardiovascular and parenchymal cells. The elevated proteolytic activity causes extracellular cleavage of multiple receptor types, such that cleavage of one receptor type leads to loss of the function carried out by this receptor. Proteolytic cleavage of the extracellular domain of the β2 adrenergic receptor in arteries and arterioles causes vasoconstriction and elevation of the central blood pressure while cleavage of the extracellular domain of the insulin receptor leads to insulin resistance and lack of transmembrane glucose transport. A diverse set of cell dysfunctions in the spontaneously hypertensive rat are accompanied by cleavage of the membrane receptors that are involved in these functions. Chronic inhibition of the unchecked protease activity in the spontaneously hypertensive rat serves to restore the extracellular receptor density and alleviates the corresponding cell dysfunctions. The mild unchecked proteolytic activity in the spontaneously hypertensive rat points towards a chronic autodigestion process as a contributor to the end organ injury encountered in this rat strain. The presence of various soluble receptors, which consist of extracellular fragments of membrane receptors, in the plasma of hypertensive and diabetic patients suggest that the autodigestion process may also be present in man.
The molecular mechanisms of hyperglycemia‐induced insulin resistance and diabetes were investigated in rats receiving a continuous glucose‐infusion. Rats accommodated systemic glucose oversupply and developed insulin resistance on day five and diabetes on day 15. In the insulin resistant rats, protein and basal activity of phosphatidylinositol (PI) 3‐kinase and protein kinase B (PKB) in skeletal muscle were unchanged, whereas insulin‐induced PI 3‐kinase and PKB/Akt activity were impaired compared with controls. The effect of glucose‐infusion on protein kinase Cζ (PKCζ) activity was independent of changes in PI 3‐kinase activity. Activated PKCζ was mainly located in the cytosol of muscle after five days of glucose‐infusion and contributed to translocation of GLUT4 to plasma membrane (PM), which maintained normoglycemia. After 15 days of glucose‐infusion, PKCζ moved from cytosol to PM. This led to an increase in the association between PKCζ and PKB and a decrease in PDK1‐PKB reactions in the PM, which inhibited PKB activity. The activity of PKCζ per se was also compromised. The reduced activity of PKCζ and PKB resulted in blunted translocation of GLUT4, which eventually led to hyperglycemia and diabetes. Thus, translocation of PKCζ may play a central role in the development of insulin resistance and diabetes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.