Regular exercise has been recommended to improve both quality and quantity of life in different clinical settings. The importance of fitness for a healthier life is particularly important nowadays, since the modern society tends to underestimate the time spent sitting in front of device screens, with almost two billion of physically inactive subjects worldwide (1). From being nomadic hunter gatherers, we became settled agriculturalists. Nowadays, we tend to spend even less time outdoor with many works are now available online and can be done at home using an internet connection. In this context, the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic did not help. Epidemiological data report that the total amount of physical activity (PA) has progressively reduced in the last decades (2), meanwhile the number of obese subjects almost tripled worldwide (3). Obesity is a well-known cardiovascular risk factor and is associated with a high number of comorbidities involving most organs of our bodies.

However, physical activity might be aerobic or anaerobic. The aerobic training consists in exercises involving large group of muscles in a rhythmic and dynamic manner for a long time, while the anaerobic training in a more intense activity, exerted in a shorted time, and involving a restricted group of muscles (4). Even though, the aerobic physical exercise has always been regarded as healthier and therefore preferable, recent evidence shows that both aerobic and anaerobic physical activity may have beneficial effect on the cardiovascular system (4). Regular PA has protective effects against cardiovascular diseases and all-cause mortality (5) and atherosclerosis is negatively modulated by regular exercise (6). Even slight increase of daily amount of PA, in the magnitude of 30 min of light- to vigorous-intensity PA per day can significantly improve cardiovascular health (7). Greater results are obtained with regular high-intensity exercise training (8).

Our body has a greater ability to face PA and starvation periods rather than an excess of caloric intake and sedentarism. We have many hormonal pathways that can mobilize depots and increase circulating glucose and lipid levels, instead the machinery to reduce their levels is rather limited. As a result, the excess of caloric intake associated with low exercise training favor the development of metabolism impairment. The direct consequence is the slowly progression toward the so-called “X syndrome,” better known as the metabolic syndrome. This syndrome is associated with several cardiovascular diseases (9) and sudden cardiac death (10). CV prevention therefore finds a cornerstone in strategies aiming at regulating lipid levels by reducing low-density lipoprotein cholesterol (LDL-C) and increasing high-density lipoprotein cholesterol (HDL-C). PA was shown to have beneficial effects on lipid profile (with sex-related differences), especially when coupled with better dietary habits (11, 12). When this is not enough to reach the target lipoprotein levels suggested by the guidelines, pharmacological approaches including statins and PCSK9 inhibitors are suggested. In consideration of the recent paradigm for cholesterol levels “the lower the better,” the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors drugs such as alirocumab and evolocumab to reduce circulating LDL-C in patient at intermediate to very high risk is getting more and more common in the clinical practice.

PCSK9 is a serine protease whose main role is to favorite the catabolism of LDL-C receptor on the hepatocyte surface thereby reducing LDL-C internalization and increasing its circulating pool (13, 14). Reducing the PCSK9 plasma levels therefore leads to reduced circulating cholesterol levels with direct inhibitory effects on the atherosclerotic process. Yet, PCSK9 recently showed pleiotropic, non-LDL-C-mediated, effects that are nowadays known to mediate some of the anti-atherosclerotic effects of PCSK9 inhibitors (i.e., through inflammation) (15, 16). In fact, low grade inflammation is associated with PCSK9 transcription, especially in metabolic syndrome patients (17). Furthermore, inflammation favorite the expression of PCSK9 in the endothelial cells and vascular smooth muscle cells (18).

Whether PCSK9 mediates some of the beneficial effects of PA on plasma lipoproteins remains to be fully investigated. Recent evidence showed that PCSK9 plasma levels are regulated by regular exercise in both animal models and humans, as reported in Table 1. Although, the strength of this association and the possible pathways are not precisely described. The purpose of this review is to highlight the role of exercise training on PCSK9 plasma levels, as a prevention strategy against atherosclerosis. We searched PubMed and Web of Science for the following keywords: “proprotein convertase/subtilisin kexin type,” “PCSK9” in combination with “exercise” and “physical activity.” Additionally, a list of recent pre-clinical and clinical studies concerning this topic is reported as a table and discussed.

Exercise training consists in a structured and repetitive PA that is practiced regularly. As longtime known, the amount and the quality of exercises and trainings can determine different results ranging from beneficial to even negative results in different settings (29). As a result, one of the major pitfalls in comparing different trials is due to the different type, intensity, and duration of the exercise protocol. Concerning the effect of exercise on cholesterol, several preclinical (30–32) and clinical studies (33–35) found an amelioration of the lipid plasma profile via regular exercise, especially aerobic one.

The modulation of circulating LDL-C in trained animals and humans relates to the adaptation of the body toward a higher metabolic state. Accordingly, the effects of exercise can be seen even acutely. Immediately after PA, LDL-C plasma levels decreases (36, 37). After termination, LDL-C levels tend to return to their basal levels, yet with regular exercise they remain lower on the long-term (38). Concerning the abovementioned adaptations, a higher metabolic state associates with a reduction of PCSK9. Consequently, the reduced catabolism of LDL receptor, increases the uptake of circulating LDL thereby reducing circulating cholesterol levels. Accordingly, recent evidence showed that PA increases the amount of hepatic LDL-C receptor (19, 39). Table 1 summarizes the main evidence proving an effect of PA on PCSK9 levels. As most studies agree on a beneficial lowering effect, an augmentation of PCSK9 levels may coexist together with LDL-C reduction in well-trained people (27). Such mixed effect might be due to many limitations in the analysis and interpretation of the studies. Furthermore, the amount of evidence concerning this topic remains quite limited.

Regular exercise is known to ameliorate lipid profile and represent the cornerstone of cardiovascular prevention. Patient that practice regular exercise show a non-negligible reduced risk of developing atherosclerosis and possible cardiovascular events. The relationship between PCSK9 and PA can be a possible explanation with exercise training envisaging a non-pharmacological PCSK9 inhibitor. Indeed, the reduction of adiposity and molecules like LOX-1, annexin A2, fibroblast growth factor 21, and resistin secondary to exercise favor the reduction of PCSK9 in the bloodstream. Yet, at present, several limitations impact on the interpretation of the results including the difficult standardization of exercise protocols.

AT conceived and drafted the manuscript. FM and LL revised it for important intellectual content. All authors read and approved its final version.

LL received a research grant from the Swiss Heart Foundation.

Author LL is co-inventor on the International Patent WO/2020/226993 filed in April 2020; the patent relates to the use of antibodies which specifically bind interleukin-1α to reduce various sequelae of ischemia-reperfusion injury to the central nervous system. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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