Control of hypertension is arguably one of the best success stories for small molecule drug development relevant to aging, emerging from an era prior to any meaningful attempt to address the root causes of age-related conditions. The results are about the best one could expect from this compensatory manipulation of cell behavior, in that the problem of high blood pressure can be made to go away in a sizable portion of patients, with an acceptable profile of side-effects. This is in large part an outcome that results from the nature of the regulation of blood pressure, in which multiple very different systems exhibit multiple very different avenues for changing their behavior. One can pick and choose from ways to target the kidney’s regulation of blood volume, the dilation of vascular smooth muscle, or even heart rate if the goal is to reduce blood pressure.
Despite the present range of antihypertensive drugs, or perhaps because of it given that investment tends to cluster in areas in which success is already proven, research and development continues apace. Considerable funding and effort is devoted to building the foundations of incrementally better antihypertensive drugs, based on an improved understanding of the regulation of blood pressure and the various proteins involved in that complex process. Today’s research materials are one example of many.
Yet still, none of this panoply of programs and therapies target the underlying causes of hypertension, the damage and dysfunction of aged tissues that gives rise to manifestations such a raised blood pressure. Those underlying causes continue to cause other harms, and aging progresses. If control by compensation is all that can be achieved, then that is what should be done. But far better approaches to age-related disease can be produced in principle, actual rejuvenation therapies that will treat age-related conditions by removing their causes.
Key protein ACE2 could protect against high blood pressure and diabetes
Researchers analysed nine key proteins in over 45,000 blood samples from the UK Biobank. ACE2 levels were increased in individuals with a diagnosis of high blood pressure or diabetes, both of which are risk factors for heart disease. The effect was seen particularly in females and was influenced by changes in genes that are associated with diabetes. Using a genetic analysis method called two-sample Mendelian randomisation, the researchers found evidence that these higher ACE2 levels may, in fact, be trying to protect against high blood pressure and type-2 diabetes. ACE2 breaks down angiotensin II, a compound that tightens blood vessels, and produces substances that relax blood vessels. In this way, the elevated levels of ACE2 seen in individuals with high blood pressure may be compensatory, by helping to relax constricted blood vessels.
ACE inhibitors are common drugs for treating high blood pressure and work by blocking the ACE1 protein which, in contrast to ACE2, makes angiotensin II. These findings could influence how ACE inhibitor drugs are used and by which patients, as it’s likely that ACE2:ACE1 balance has a role in how successful ACE inhibitors are in treating blood pressure. Individuals with naturally altered levels of ACE2 may be better suited to certain ACE inhibitors, and this may lead to more tailored treatments based on blood ACE2 levels. Future research will explore whether increasing ACE2 activity or mimicking its effects could improve treatment for high blood pressure and diabetes. Previous preclinical studies of a common anti-diabetic drug, metformin, showed that it increases ACE2 expression as part of its action.
Circulating Cardiovascular Proteomic Associations With Genetics and Disease
To understand the relationships between circulating biomarkers and genetic variants, medications, anthropometric traits, lifestyle factors, imaging-derived measures, and diagnoses of cardiovascular disease, we undertook in-depth analyses of measures of 9 plasma proteins with a priori roles in genetic and structural cardiovascular disease or treatment pathways (ACE2, ACTA2, ACTN4, BAG3, BNP, CDKN1A, NOTCH1, NT-proBNP, and TNNI3) from the Pharma Proteomics Project of the UK Biobank cohort (over 45,000 participants sampled at recruitment).
We identified significant variability in circulating proteins with age, sex, ancestry, alcohol intake, smoking, and medication intake. Phenome-wide association studies highlighted the range of cardiovascular clinical features with relationships to protein levels. Genome-wide genetic association studies identified variants near GCKR, APOE, and SERPINA1, that modified multiple circulating protein levels (BAG3, CDKN1A, and NOTCH1). NT-proBNP and BNP levels associated with variants in BAG3. ACE2 levels were increased with a diagnosis of hypertension or diabetes, particularly in females, and were influenced by variants in genes associated with diabetes (HNF1A and HNF4A). Two-sample Mendelian randomization identified ACE2 as protective for systolic blood pressure and type-2 diabetes.
