Animal studies show that rapamycin has great therapeutic potential to inhibit atherosclerosis.
Frequently, the first sign of cardiovascular disease is sudden death. This is called unheralded myocardial infarction. The problem is sudden "plaque rupture" or destabilization of an asymptomatic atheroma. 650,000 Americans die each year from heart disease: 1.2 million have heart attacks, killing 450,000; 300,000 die suddenly before reaching the hospital and about half had no prior warning.
Atherosclerosis starts early; but doesn't kill until aging causes destabilization. In Vietnam war, 45% of soldiers who had autopsy examination of coronary arteries had evidence of atherosclerosis. By age 40-49, 70% have coronary artery disease. However, heart attack is mainly a disease of men over 60 and women over 75. Incidence of fatal hart attacks in men and women is: 3%, 2% in age group 44-59; 11%, 4%, in age group 60-79 and 17%, 9% in age group 80+.
1 out of every 3 deaths in U.S. reported in 2015, were caused by cardiovascular disease; so there is clearly no effective treatment.
Research in animal models have shown how rapamycin blocks atherosclerosis on a cellular level. The following 6 papers are selected as examples and the last three (Ma 2007, Zhao 2009, Chen 2008), and are recommended for study.
"Potential therapeutic effects of mTOR inhibition in atherosclerosis", Kurdi, 2015 states, "mTOR has been identified as a pre-eminent factor in the development of atherosclerosis"..."rapalogs have shown undeniable evidence of the value of mTOR inhibition to prevent the development of atherosclerotic plaques in several animal models."
"Everolimus-induced mTOR inhibition selectively depletes macrophages in atherosclerotic plaques by autophagy," Martinet, 2007; "Macrophages ...play a pivotal role in plaque destabilization...macrophages in vascular wall can be cleared via induction of autophagy by mTOR inhibition."
"Autophagy in Atherosclerosis, Martinet, 2009; "Because atherosclerosis is an inflammatory disorder of the arterial intima, pharmacologic approaches could be developed to stabilize vulnerable, rupture-prone lesions through selective induction of macrophage autophagic death."
In promotion of atherosclerosis the main actors are:
1. The vascular smooth muscle cells: Under stimulation mTOR become hyperfunctioning senescent cells with multiple functions that promote atherosclerosis.
2. Monocytes/macrophages: migrate to lesion and promote inflammation; blocked by rapamycin and decreased by autophagy.
3. Lipids: Influx promotes atheroma; rapamycin causes efflux and removal atherosclerosis.
4. Chronic inflammation: ramamycin decreases chronic inflammation by reduction of pro-inflammatory cytokines by blocking their messenger RNA synthesis.
5. Collagen, required for stabilization of plaque; rapamycin increases collagen by decreased catabolism of collagen by reduced expression of metalloproteases (MMP) which dissolve collagen.
"Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells", Kun Ma, 2007; Sirolimus prevents lipid accumulation in vascular smooth muscle cells, reduces cytokine production.
"Low-dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking LDL receptor", Zhao, 2009; "at low doses, sirolimus was an effective and safe anti-atherogenic agent...it attenuated the progression of atherosclerosis...by reducing the pro-inflammatory vascular response typical of the disease."
"Oral rapamycin attenuates inflammation and enhances stability of atherosclerotic plaques in rabbits independent of serum levels", Chen, 2008; "Oral administration of rapamycin effectively attenuated inflammation, inhibited progression and enhanced stability of atherosclerotic plaques, without altering serum lipid levels. Our findings suggest a novel approach to treatment of atherosclerosis."
In animal studies rapamycin is the most effective drug in preventing progression of atherosclerosis and preventing destabilization of plaque, a major cause of acute myocardiial infarction and sudden death.
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