- Studies show that the longevity-associated variant (LAV) of BPIFB4 the gene is associated with longer life in humans and has protective effects in rodent models of cardiovascular disease.
- That’s what a new study shows LAV-BPIFB4 may exert its cardioprotective effects by promoting the formation of new blood vessels and reducing the number of blood vessel cells that have become old and have stopped proliferating.
- The study shows that inducing the expression of LAV-BPIFB4 in adult mice, improved cardiac function and regulation of blood flow to the heart.
- These findings highlight the therapeutic potential of LAV-BPIFB4 to mitigate the adverse effects of aging on cardiovascular function.
A recent study published in Cardiovascular studies assumes that LAV-BPIFB4A gene variant that previous research has shown to be highly expressed by extremely long-lived individuals may also protect heart and vascular function in old age.
In the new study, inducing the expression of LAV-BPIFB4 in aged mice led to improvements in cardiac function that, translated to the human context, would be equivalent to reducing the biological age of the heart by 10 years.
Study author Dr Paolo Madedu, professor of experimental cardiovascular medicine at the University of Bristol in the UK, said Medical News Today:
“It is known that centenarians can pass on their healthy genes to their offspring. This research demonstrates that it is also possible to make human heart cells younger and older mouse hearts by transferring a gene expressed by centenarians. We also demonstrate that the benefit is related to the gene’s ability to reprogram cardiac cells to become more resistant to stress and build the mechanism (
ribosomes), which produce proteins.
The heart has four chambers – two upper chambers called atria, which receive blood from the body, and two lower chambers, called ventricles, which pump blood to the body.
The right atrium receives deoxygenated blood from the body and the right ventricle pumps the deoxygenated blood to the lungs. The left atrium receives oxygen-rich blood from the lungs, which is then pumped into the left ventricle.
As the left ventricle contracts, oxygenated blood is transported to the rest of the body. The very functioning of the heart requires oxygen and nutrients, which are supplied by the coronary arteries.
Aging is associated with an increased risk of cardiovascular disease, including heart attack, heart failure, and diabetes
These changes include an increase in the thickness and stiffness of the walls of the coronary arteries and the left ventricle. Left ventricular thickening, known as
Another change associated with aging involves the dysfunction of
Endothelial cells regulate blood flow as well as the exchange of fluids and molecules between blood and tissue. Endothelial cell dysfunction leads to narrowing of the arteries and can increase the risk of cardiovascular disease.
Endothelial cells also play an important role in angiogenesis, the process of forming new blood vessels from pre-existing ones. Endothelial dysfunction during aging is also associated with
Thus, endothelial cell dysfunction can lead to a decrease in blood supply to the heart muscle from the coronary arteries, thereby increasing the risk of heart attack or myocardial infarction.
Although the evidence is mixed,
Previous studies have shown that some individuals have extremely long lives and this trait is hereditary. These long-lived individuals tend to show delayed aging and have a lower incidence of cardiovascular disease.
Additionally, these longer-lived individuals had higher circulating levels of LAV-BPIFB4.
In addition to being present in the blood, BPIFB4 is also expressed by endothelial cells, cardiomyocytes or heart muscle cells, and some immune cells.
Causing expression of LAV-BPIFB4 in older mice it may reduce
In the current study, the researchers first investigated the potential mechanisms underlying the protective effects of LAV-BPIFB4 in cardiovascular conditions.
They examined the differences in hearts obtained from adult ischemic heart failure patients undergoing heart transplantation and those from individuals who died of causes other than cardiovascular complications.
Hearts obtained from patients with ischemic heart failure showed lower expression levels of BPIFB4 in cardiomyocytes and endothelial cells than in individuals with healthy hearts. Hearts from patients with ischemic failure also have a lower capillary density than healthy hearts.
Furthermore, there is a reduction in pericyte density and lower pericyte vascular coverage in hearts obtained from patients with ischemic heart failure.
Among patients with ischemic heart failure, individuals expressing the LAV variant of BPIFB4 of both chromosomes show a higher density of pericytes and greater coverage of capillaries by pericytes than those carrying one or no copies of LAV-BPIFB4 gen.
However, these groups did not differ in capillary density, suggesting LAV-BPIFB4 preserves the pericyte coating of capillaries without affecting capillary density.
Pericytes isolated from the hearts of patients with ischemic heart failure showed greater expression of markers of oxidative stress and
The researchers found that the addition of LAV-BPIFB4but not other forms of BPIFB4to cultured pericytes isolated from the heart of patients with ischemic heart failure reduced the expression of markers of aging and oxidative stress.
Pericytes from the hearts of patients with ischemic failure also show down-regulation of the protein synthesis machinery, which is associated with cellular senescence. The addition of LAV-BPIFB4 led to an upregulation of the protein synthesis machinery in pericytes isolated from the hearts of patients with ischemic heart failure.
Previous studies have shown that endothelial cell senescence is associated with impaired angiogenesis. In subsequent experiments performed with endothelial cell cultures, LAV-BPIFB4 increases the ability of senescent endothelial cells to form new blood vessels to a greater extent than others BPIFB4 options.
LAV-BPIFB4 also increases the secretion of molecules that promote angiogenesis from pericytes isolated from the hearts of patients with ischemic heart failure.
Preincubation of pericytes from patients with ischemic heart failure LAV-BPIFB4 also enhances the ability of these pericytes to support the formation of new blood vessels from senescent endothelial cells.
These results suggest that LAV-BPIFB4 can directly improve the ability of senescent endothelial cells to form new blood vessels, as well as indirectly by promoting the secretion of molecules from pericytes that act on endothelial cells. In other words, LAV-BPIFB4 the gene may help restore deficits in the function of old vascular cells.
In their previous work, the study authors showed that the delivery of LAV-BPIFB4 the use of a viral vector, which involves the use of a harmless virus carrying the gene of interest, can improve protein expression in the heart of a mouse model of diabetes.
In the present study, the authors presented both LAV-BPIFB-4 or different BPIFB4 variant of middle-aged and old mice using a viral vector.
Aged mice show a decline in cardiac function at baseline compared to middle-aged mice. The delivery of LAV-BPIFB4 in middle-aged and old mice, it was associated with an improvement in left ventricular function.
Aging is also associated with a decrease in the ability of coronary artery blood flow to meet the demands of the heart muscle in response to exercise or stress. This is described in terms of coronary blood flow reserve, which is the ratio of the maximal increase in coronary blood flow in response to stress to coronary blood flow at baseline.
To simulate the heart’s response to stress, the researchers used dobutamine, a drug that mimics the effects of beta-adrenaline released during stress.
Treatment with LAV-BPIFB4 increased coronary blood flow at baseline and in response to dobutamine in both middle-aged and older rats. This suggests that LAV-BPIFB4 could help restore deficits in coronary blood flow in response to stress.
These improvements in cardiac function after LAV-BPIFB4 treatment was accompanied by an increase in blood vessel and pericyte density and pericyte coverage in the hearts of middle-aged and older mice, while reducing the number of senescent cells.
In addition to cardiomyocytes, cardiac tissue also consists of fibroblasts, nerve endings, and immune cells. These cells are embedded in an extracellular matrix secreted by fibroblasts. The extracellular matrix is composed of collagen and other proteins and plays a key role in maintaining the structure and function of the heart.
Conditions such as aging and heart failure are associated with cardiac fibrosis, involving excess collagen deposition in the extracellular matrix.
Cardiac fibrosis leads to stiffness of the heart walls and deterioration of heart function. In the present study, LAV-BPIFB4 treatment reduced levels of myocardial fibrosis in the hearts of adult mice.
These results suggest that LAV-BPIFB4 may moderate the effects of aging on cardiac function and structure.
“This is still early-stage research but could one day provide a revolutionary way to treat people with heart failure and even stop the debilitating condition from progressing,” said Prof James Leiper, associate medical director at the British Heart Foundation, which provided the research funding.