Relating Warfarin, Vitamin K, and Cellular Senescence in the Progression of Aortic Calcification

Calcification of blood vessel walls progresses with age, an issue that sees cells behave as through they are in bone tissue, a maladaptive reaction to the altered signaling environment and damage of aged tissue. The resulting deposition of calcium makes normally flexible cardiovascular tissue stiff and dysfunctional, ultimately contributing to disease and death.

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Evidence has accumulated in recent years for the accumulation of senescent cells to be an important contributing factor to calcification. Senescent cells grow in number with age and secrete the senescence-associated secretory phenotype (SASP), signals that rouse the immune system to inflammation and cause harmful alterations in the behavior of other cells.

There is an established body of work regarding factors that affect the progression of calcification, such as chronic use of the anticoagulant warfarin (unfavorable) and vitamin K intake (favorable). Given the better and broader understanding lately emerged in the research community of the relevance of cellular senescence to aging, a great deal of retrofitting of old theories and data is presently taking place. Today's open access paper is an example of this sort of work, in which links are established between the SASP and long-established risk factors for calcification revolving around the role of vitamin K and treatments like warfarin that reduce vitamin K levels.

Warfarin Accelerates Aortic Calcification by Upregulating Senescence-Associated Secretory Phenotype Maker Expression

Aortic calcification (AC) is a pathological condition with increasing prevalence of morbidity and mortality. AC is a process of osteoblast-like cell accumulation in the muscular layer of arteries. Enhanced stiffness of the arteries in AC might lead to severe vascular complications in the brain, heart, and kidneys. AC is a strong, independent predictor of cardiovascular disease (CVD) and cardiac adverse events. The present study demonstrated that the association of warfarin use with AC differs in different age groups of patients. Specifically, warfarin adversely affects younger (<65 years) patients more than older (≥65 years) patients, and this is possibly due to the fact that warfarin-associated senescence was more sensitive in younger patients. In vitro study also revealed that young VSMC are more sensitive to warfarin-induced low-grade calcification.

It has been observed that there is a systemic increase level of secreted proteins with aging, which contain several proinflammatory cytokines, chemokines, tissue-damaging proteases, and growth factors. These secreted factors affect the microenvironment of tissue, in which they could propagate the stress response and regulate neighboring cells. These phenotypes are termed the senescence-associated secretory phenotype (SASP). The SASP is a critical intrinsic characteristic of cellular senescence resulting in a chronic low-grade state of inflammation that has been implicated in the development of several chronic diseases of aging including AC. Among SASP, cytokines and growth factors are important in the differentiation of senescent VSMC into calcified cells.

we conducted a case-cohort study within the Multi-Ethnic Study of Atherosclerosis (MESA); 6,655 participants were included. From MESA data, we found that AC was related to both age and vitamin K; furthermore, the score of AC increased with SASP marker including interlukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) rising. Next, a total of 79 warfarin users in our center developed significantly more calcified coronary plaques as compared to non-warfarin users. We investigated the role of warfarin in phosphate-induced AC in different ages by in vitro experimental study. Furthermore, dose-time-response of warfarin was positively correlated with AC score distribution and plasma levels of the SASP maker IL-6 among patients younger than 65 years, but not among patients older than 65 years. In addition, in vitro research suggested that warfarin treatment tended to deteriorate calcification in young VSMC at the early stage of calcification. Our results suggested that aging and warfarin-treatment were independently related to increased AC. Younger patients were more sensitive to warfarin-related AC than older patients, which was possibly due to accumulated warfarin-induced cellular senescence.

In the MESA, we discovered that the accumulated intake of vitamin K was negatively related to AC, which demonstrated that warfarin may aggravate AC by downregulating the level of vitamin K in plasma. In addition, IL-6 and TNF-α levels were positively correlated with AC. When we divided individuals depending on vitamin K intake and analyzed the relationship among vitamin K, AC, and SASP, results showed that Agatston score (a measure of AC) and SASP level decreased with the increase of vitamin K intake.

Source: Fight Aging!