7-ketocholesterol Accumulation Speeds Calcification of Blood Vessels
Researchers here link vascular calcification in aging with an accumulation of one of a number of related forms of undesirable metabolic waste. One of the root causes of degenerative aging is this accumulation of hardy forms of metabolic waste that our biochemistry either finds hard to break down, or simply cannot break down. This waste accumulates in cell lysosomes as a mix of compounds usually called lipofuscin or drusen, depending on the context. Lysosomes are the recycling plants of the cell, and this accumulation causes them to become dysfunctional, leading ultimately to some form of garbage catastrophe as cellular maintenance breaks down. The SENS Research Foundation is one of the few groups funding work to find ways to safely remove lipofuscin compounds, largely based on mining the bacterial world for enzymes that can be used as the basis for small molecule drugs. Once developed, clearing lipofuscin will be a form of rejuvenation therapy, removing one of the contributing causes of a number of age-related conditions.
One of the constituent compounds of liposfuscin is 7-ketocholesterol, which is known to contribute to macular degeneration as well as to various forms of damage to blood vessel walls, such as those that can lead to atherosclerosis. The SENS Research Foundation has had some success in finding candidates to digest 7-ketocholesterol, but this is still a work in progress. The research noted here provides yet another argument for the research community to invest more time and funding into finding ways to effectively break down these harmful lipofuscin constituents: vascular calcification contributes to the development of a range of ultimately fatal cardiovascular conditions.
Vascular calcification, characterized by the deposition of hydroxyapatite in cardiovascular tissue, is commonly observed in patients with diabetes mellitus, chronic kidney disease (CKD) and atherosclerosis. Several studies have indicated that the presence of calcification in coronary arteries correlates with an increased risk of myocardial infarction and is an independent predictor of future cardiovascular events in asymptomatic patients. Accordingly, treatment of vascular calcification is directly linked to decreased cardiovascular mortality. Recent findings suggest that the development of calcification is an active cell-regulated process similar to osteogenesis. Two pathological processes, osteoblastic differentiation and apoptosis of vascular smooth muscle cells (VSMCs), are mainly involved in the development of vascular calcification.
Recent studies have showed that oxidized low-density lipoprotein (oxLDL), enriched in atherosclerotic plaques, promotes osteoblastic differentiation and calcification of VSMCs. Oxysterols, such as 7-ketocholesterol (7-KC), are major components of oxLDL and are associated with its cytotoxicity. We have previously reported that 7-KC promotes osteoblastic differentiation and apoptosis of VSMCs, resulting in progression of calcification. However, whether the effects of 7-KC on calcification are related to autophagy is still unknown. Our aim was therefore to unravel the relationship between ALP and the progression of calcification by 7-KC.
The formation and accumulation of 7-KC often occur in lysosomes, and 7-KC promotes accumulation of unesterified cholesterol in the lysosome. Accumulation of cholesterol causes impairment of the lysosomal membrane, resulting in inhibition of the lysosome fusing with the autophagosome or endosome. Because 7-KC is also known to induce permeabilization of the lysosomal membrane, impairment of autophagy process by 7-KC may due to alteration of the lysosomal membrane potential. Subsequent to autophagy disruption, 7-KC causes the failure of lysosomal enzyme activity along with enlargement of lysosomes.
In our model, a high concentration of 7-KC caused further increase in calcification, and this exacerbation of calcification was closely related to apoptosis. In contrast, a low concentration of 7-KC accelerated calcification without apoptosis, and this acceleration of calcification was alleviated by inhibition of lysosomal-dysfunction-dependent oxidative stress. Recent studies have indicated that 7-KC induces the loss of mitochondrial transmembrane potential which is a marker of mitochondrial injury. Moreover, the decline of lysosomal function causes the defect of mitochondrial turnover, which induces the acceleration of reactive oxygen species (ROS) generation. These lysosomal-mitochondrial axes also induce the interaction between ROS generated from mitochondria and iron derived from lysosome, leading to the intralysosomal accumulation of more reactive ROS. In conclusion, we showed for the first time that 7-KC induces oxidative stress via lysosomal dysfunction, resulting in exacerbation of calcification.