There have been a number of life science discoveries of late that might lead to therapies capable of reducing the level of tissue damage caused by structural failures in important blood vessels, the basis for a range of age-related conditions. News of another possible approach arrived recently, and you will find links to the publicity materials and open access paper below. Blood vessel failures cause an interruption of oxygenated blood flow to tissues, and depending on the location in the body and size of the failed vessel, can produce the dramatic symptoms of stroke, heart attack, and so forth. While methods of prevention are far preferable to methods the produce greater than normal resilience, if the resilience is on offer it would be foolish to turn it down.
In ischemic injuries where blood flow is lost for a period of time, the real damage is done not after blood supply ceases, but after it is restored. With renewed oxygenation, cells fall into a self-sabotaging state of intense activity and die in large numbers. Of course if blood supply is never restored, the same end result occurs and the tissue dies, but reperfusion injury is perhaps the biggest threat in stroke, heart attack, and the like. Thus there is great interest in the research community in finding ways to reduce this damage, and many different methodologies have been tried, sadly to little success. Now that researchers are getting a better handle on the cellular biochemistry of ischemia and reperfusion, however, targets are emerging. For example, suppressing the oxygen sensor PHD1 greatly reduces reperfusion damage, as fewer cells react inappropriately to the return of oxygenated blood. Similarly, temporary sabotage of the cell death process might achieve a similar outcome, while letting the cells otherwise react normally, and MIF is one target there. Another possible approach is to spur greater growth of alternative vasculature via Rabep2, so as to reduce the impact of any one path for blood failing. As you can see, there are many possible points at which to intervene.
Still, prevention seems a whole lot better. When the problem is failing aged blood vessels, the solution has to be something like the SENS approach to rejuvenation research. Taking the proximate causes of blood vessel failure, that include hypertension, loss of elasticity in blood vessels, and atherosclerosis, for example, we can the look at the root causes of these issues. These include cross-linking in the extracellular matrix of blood vessel walls, rising numbers of senescent cells, and the oxidized lipids produced as a result of cells taken over by malfunctioning mitochondria. Each of these root cause classes of cell and tissue damage has an associated path to therapies that will repair or work around this type of damage to remove its effects. The programs are as clearly mapped out as anything can be in the world of research and development. If we want to see an end to strokes and heart attacks, a world in which older people have great cardiovascular health with little to no decline beyond their earlier years, then this is the type of research we need to support.
The inability of cells to eliminate damaged proteins and organelles following the blockage of a coronary artery and its subsequent re-opening with angioplasty or medications - a sequence known as ischemia/reperfusion - often results in irreparable damage to the heart muscle. To date, attempts to prevent this damage in humans have been unsuccessful. According to a new study, however, it may be possible to substantially limit reperfusion injury by increasing the expression of a protein known as Bcl-2-associated athanogene 3 (BAG3).
Ischemia impairs the function of cellular organelles including mitochondria, the cell's energy-producers, resulting in harmful effects that set the stage for a sudden burst in the generation of toxic oxidizing substances when oxygenated blood reenters the heart. The toxins lead to fundamental changes in the biology of the heart. Notably, they activate cell death pathways and decrease autophagy - the process by which cells remove malfunctioning proteins and organelles. Autophagy plays a critical role in removing damaged myocardial cells (the muscular tissue of the heart) and misfolded heart muscle fibers. The new work shows that BAG3 expression both inactivates cell death pathways, helping prevent the loss of heart cells triggered by ischemia, and activates autophagy, thereby enabling cells to clear out impaired components of the heart cell before they inflict extensive damage.
In initial work, the research group found that BAG3 promotes autophagy and inhibits programmed cell death (apoptosis) in cultured cardiac myocytes. Subsequently, they found that when heart cells were exposed to the stress of hypoxia/reoxygenation or when living mice were stressed with ischemia/reperfusion, they suffered dramatic reductions in BAG3 expression. Those paradoxical changes in BAG3 levels turned out to be directly associated with increases in biomarkers of autophagy and with decreases in biomarkers of apoptosis. By artificially knocking down BAG3 in mouse heart cells, the researchers were able to produce an apoptosis-autophagy biomarker phenotype nearly identical to that produced by hypoxia/reoxygenation. By contrast, BAG3 overexpression normalized apoptosis and autophagy. In a key experiment, the team further showed that tissue damage sustained following ischemia/reperfusion could be substantially reduced by treating mice with BAG3 prior to vessel re-opening. BAG3 overexpression before the onset of ischemia/reperfusion also resulted in normalization in apoptosis and autophagy biomarkers.
BAG3 has come to the attention of investigators focused on the heart due to the observation that mutations in BAG3 lead to familial dilated cardiomyopathy, the finding that BAG3 modulates excitation-contraction coupling in the heart, and our recent observation that BAG3 promoted mitochondrial degradation through the autophagy-lysosome pathway and through direct interactions with mitochondria. Because disruption of the normal removal of damaged and dysfunctional mitochondria plays a pivotal role in reperfusion injury following ischemia, we hypothesized that alterations in the expression or function of BAG3 might play a role in reperfusion injury.
The role of autophagy and apoptosis in the development of cardiovascular disease and in particular in the development of heart failure has been well recognized. In fact, modest overexpression of active caspase leads to the development of heart failure. However, a pivotal role for BAG3 in regulating cardiac protection and its associated effects on autophagy and apoptosis have not been previously recognized. Importantly, while restitution of diminished levels of BAG3 after hypoxia/reoxygenation or ischemia/reperfusion lead to salutary effects in cells or tissues that have been stressed, BAG3 appears to have no untoward effects on either autophagy or apoptosis when BAG3 levels are increased in cells or hearts that have not been exposed to stress, suggesting that attempts to increase BAG3 levels could provide a unique and important therapeutic approach to cardiac protection.
Despite successful efforts to limit the time between the onset of coronary obstruction and coronary intervention in patients with an acute myocardial infarction, myocardial damage due to reperfusion injury remains a major clinical problem that has failed to be influenced by multiple pharmacologic approaches. The findings that BAG3 levels are reduced during the stress of hypoxia/reoxygenation in vitro or ischemia/reperfusion in vivo and that overexpression of BAG3 reduces infarct size and improves left ventricle function after ischemia/reperfusion in mice suggest that BAG3 could provide a therapeutic target for cardiac protection. We recognize that biological differences exist between mice and humans, and it will be important to demonstrate that similar salutary benefits of enhancing BAG3 levels can be seen in a large animal model of ischemia/reperfusion injury. Nonetheless, our results suggest that moving from evaluations in mice to studies in large animals with ischemia and reperfusion, the next step in translational science paradigm, would be warranted.