Pathological mechanisms of cigarette smoking, dietary, and sedentary lifestyle risks in vascular dysfunction: mitochondria as a common target of risk factors

Abstract

In the past century, the lifespan of the human population has dramatically increased to the 80 s, but it is hindered by a limited health span to the 60 s due to an epidemic increase in the cardiovascular disease which is a main cause of morbidity and mortality. We cannot underestimate the progress in understanding the major cardiovascular risk factors which include cigarette smoking, dietary, and sedentary lifestyle risks. Despite their clinical significance, these modifiable risk factors are still the major contributors to cardiovascular disease. It is, therefore, important to understand the specific molecular mechanisms behind their pathological effects to develop new therapies to improve the treatment of cardiovascular disease. In recent years, our group and others have made a progress in understanding how these risk factors can promote endothelial dysfunction, smooth muscle dysregulation, vascular inflammation, hypertension, lung, and heart diseases. These factors, despite differences in their nature, lead to stereotypical alterations in vascular metabolism and function. Interestingly, cigarette smoking has a tremendous impact on a very distant site from the initial epithelial exposure, namely circulation and vascular cells mediated by a variety of stable cigarette smoke components which promote vascular oxidative stress and alter vascular metabolism and function. Similarly, dietary and sedentary lifestyle risks facilitate vascular cell metabolic reprogramming promoting vascular oxidative stress and dysfunction. Mitochondria are critical in cellular metabolism, and in this work, we discuss a new concept that mitochondria are a common pathobiological target for these risk factors, and mitochondria-targeted treatments may have a therapeutic effect in the patients with cardiovascular disease.

Keywords: Cardiovascular risk factors; Cigarette smoking; Metabolism; Mitochondria; Sedentary lifestyle; Vascular dysfunction.

Figure 1.

Mitochondria are the common pathophysiological target for cardiovascular risk factors which promote metabolic alterations and oxidative stress driving vascular epigenetic and phenotypic dysregulation. This increases vascular inflammation and permeability, impairs vascular relaxation, and plasticity, accelerates vascular senescence and disease.

Figure 2.

Endothelial cell-smooth muscle cell regulatory interactions and impact sites for harmful components of cigarette smoke on smooth muscle cells contractile tonus, proliferation, migration, and phenotyping changes. In addition to endothelial dysfunction, oxidative stress in smooth muscle cells is driving vascular remodeling.

Figure 3.

Multiple cardiovascular risk factors such as aging, smoking, diet, and sedentary lifestyle promote mitochondrial dysfunction which can be attenuate by lifestyle modifications, dietary supplements, NAD donors, TERT agonists and future mitochondria-targeted treatments to improve mitochondrial and vascular function.