THE AUTODIGESTION HYPOTHESIS AND RECEPTOR CLEAVAGE IN DIABETES AND HYPERTENSION

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Molecular Medicine

Background:

• Cardiovascular complications like hypertension and diabetes frequently co-occur with other conditions.
• The molecular mechanisms underlying these co-morbidities remain poorly understood and lack universal acceptance.

Purpose of the Study:

• To propose and test a novel molecular hypothesis for co-morbidities in hypertension.
• To investigate the role of unchecked proteolytic activity and receptor destruction in hypertension-related co-morbidities.

Main Methods:

• Testing the hypothesis in spontaneously hypertensive rats.
• Analyzing plasma and cell-associated matrix metalloproteinase and serine protease activity.
• Evaluating the effects of chronic protease inhibition on receptor density and cell function.

Main Results:

• Spontaneously hypertensive rats exhibit elevated proteolytic activity, leading to extracellular cleavage of multiple receptor types.
• Cleavage of the β(2) adrenergic receptor contributes to vasoconstriction and elevated blood pressure.
• Cleavage of the insulin receptor results in insulin resistance and impaired glucose transport.
• Chronic inhibition of protease activity restored receptor density and alleviated cell dysfunctions.

Conclusions:

• Unchecked proteolytic activity and subsequent receptor destruction offer a molecular basis for hypertension-related co-morbidities.
• This process may contribute to end-organ injury in hypertension.
• The presence of soluble receptors in patients suggests this autodigestion process may occur in humans.