Genetically engineered loss of ANGPTL2 has been shown to slow the progression of heart disease in mice. Lower levels of ANGPTL2 result from exercise, and higher levels are associated with greater age, greater amounts of visceral fat, and the presence of senescent cells, among other factors - all of which fits well with the range of known risk factors for heart disease. The more ANGPTL2 in circulation, the worse the outcome. This open access review paper covers what is presently known of ANGPTL2 and its role in metabolism and age-related cardiovascular disease: of interest given the past few years of research is that ANGPTL2 may be generated by senescent cells as a part of their harmful senescence-associated secretory phenotype.
Worldwide, the number of patients with heart disease is increasing as populations of elderly people expand. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are associated with adverse health outcomes that decrease a patient's well-being and productivity. Prevention of these conditions is desirable to promote healthy aging and improve patients' lifestyle. The pathologic basis of CVD is atherosclerosis caused by ectopic accumulation of cholesterol in vessel walls; thus advent of therapies aimed at reducing low-density lipoprotein (LDL)-cholesterol levels has succeeded in decreasing the number of CVD events. However, these events continue to occur, even in patients whose LDL-cholesterol levels have been lowered, indicating that the pathologies underlying CVD are highly complex.
Many of our previous studies have revealed that the expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiologic stimuli such as hypoxia, reactive oxidative species, and pressure overload. ANGPTL2 expression also increases in cells undergoing senescence, suggesting that ANGPTL2 is a SASP factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathologic states and contributes to the development of aging-associated diseases such as CVD. Thus, to understand the mechanisms underlying these conditions, we focus our discussion here on the role of ANGPTL2 in CVD.
Obesity and associated metabolic diseases predispose individuals to coronary artery disease (CAD), the major common form of CVD. In terms of the mechanisms linking these conditions, accumulating evidence suggests that inflammatory changes in perivascular fat, which is distributed ubiquitously around arteries throughout the body, may have a direct role in promoting the pathogenesis of vascular diseases accelerated by obesity. Interestingly, in obesity, chronic inflammation occurs in both visceral and perivascular adipose tissues. In obese mice, the expression of ANGPTL2 is increased in perivascular adipose tissues surrounding the femoral artery at levels equivalent to those seen in visceral adipose tissues. In mice, we have undertaken adipose tissue transplantation experiments that show that adipose tissue-secreted ANGPTL2 accelerates vascular inflammation, pathologic vascular tissue remodeling and subsequent CVD development.
Moreover, atherosclerosis progression, including plaque instability, is associated with chronic vessel wall inflammation and is a risk factor for major CAD events. Therefore, therapies designed to inhibit chronic inflammation in vessel walls should slow atherosclerosis progression. Relevant to this, ANGPTL2 is abundantly expressed in vascular endothelial cells of CAD patients. ANGPTL2 expression in endothelial cells also significantly increases in subjects predisposed to atherosclerotic disease brought on by obesity or metabolic disturbances. As expected, increases in endothelial cell-derived ANGPTL2 expression in mice promote vascular inflammation and subsequent endothelial cell dysfunction and atherosclerosis development. Vascular inflammation, which underlies atherosclerotic disease, emerges from the interplay of different cell types, including endothelial cells, smooth muscle cells, and perivascular adipocytes as resident cells, and macrophages as infiltrating cells. Macrophage-secreted ANGPTL2 also accelerates atherosclerotic disease in mice. Thus, ANGPTL2-induced chronic inflammation predisposes individuals to atherosclerotic disease and to CAD development.
Cellular senescence is defined as cell cycle arrest as a means to counteract DNA damage induced by aging and various stressors. Accumulation of senescent cells in various tissues accelerates aging and disease development. A recent report using a transgenic approach in mice demonstrated that clearance of senescent cells delays several age-associated disorders, suggesting that senescent cells promote these conditions. Interestingly, it has been reported that endothelial cells derived from smokers and exhibiting oxidative stress-induced premature senescence show significantly increased ANGPTL2 expression. Moreover, senescent fibroblasts from patients with Werner syndrome (adult progeria) show abundant ANGPTL2 expression and increased expression of other SASP factors. We have also reported that ANGPTL2 expression significantly increases in the hearts of aged compared with young mice. Thus, ANGPTL2 may function as a senescence-associated secretory phenotype in several senescent cell types. If so, markedly increased circulating ANGPTL2 levels seen in patients with chronic aging-related diseases may reflect the accumulation of senescent cells in their organs.