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Review
. 2018 Mar 10;19(3):797.
doi: 10.3390/ijms19030797.

Chemotherapeutic-Induced Cardiovascular Dysfunction: Physiological Effects, Early Detection-The Role of Telomerase to Counteract Mitochondrial Defects and Oxidative Stress

Nabeel Quryshi  1 , Laura E Norwood Toro  2 , Karima Ait-Aissa  3   4 , Amanda Kong  5 , Andreas M Beyer  6   7
Affiliations
Review

Chemotherapeutic-Induced Cardiovascular Dysfunction: Physiological Effects, Early Detection-The Role of Telomerase to Counteract Mitochondrial Defects and Oxidative Stress

Nabeel Quryshi et al. Int J Mol Sci. .

Abstract

Although chemotherapeutics can be highly effective at _targeting malignancies, their ability to trigger cardiovascular morbidity is clinically significant. Chemotherapy can adversely affect cardiovascular physiology, resulting in the development of cardiomyopathy, heart failure and microvascular defects. Specifically, anthracyclines are known to cause an excessive buildup of free radical species and mitochondrial DNA damage (mtDNA) that can lead to oxidative stress-induced cardiovascular apoptosis. Therefore, oncologists and cardiologists maintain a network of communication when dealing with patients during treatment in order to treat and prevent chemotherapy-induced cardiovascular damage; however, there is a need to discover more accurate biomarkers and therapeutics to combat and predict the onset of cardiovascular side effects. Telomerase, originally discovered to promote cellular proliferation, has recently emerged as a potential mechanism to counteract mitochondrial defects and restore healthy mitochondrial vascular phenotypes. This review details mechanisms currently used to assess cardiovascular damage, such as C-reactive protein (CRP) and troponin levels, while also unearthing recently researched biomarkers, including circulating mtDNA, telomere length and telomerase activity. Further, we explore a potential role of telomerase in the mitigation of mitochondrial reactive oxygen species and maintenance of mtDNA integrity. Telomerase activity presents a promising indicator for the early detection and treatment of chemotherapy-derived cardiac damage.

Keywords: cardiac oncology; heart failure; mtDNA damage; telomerase; telomerase activity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Differing role of telomerase within chemotherapeutic induced cellular damage (endothelial/cancer cells) and interconnectedness with cardiovascular disease. Cancer cells are the primary _targets of a wide array of chemotherapeutic agents and often contribute to the forced apoptosis of cancerous cells. Separate from its emerging role as a protective element in the mitochondria, TERT functions to regulate DNA replication and proliferation in the nucleus.
Figure 2
Figure 2
Hypothesized therapeutic nature of telomerase to preserve mitochondrial and endothelial function, therefore mitigating cardiovascular disease phenotypes, distinct from its previously detailed oncogenic role (gene expression regulation/telomere maintenance). TERT is known to control telomerase activity as well as regulate gene expression. Through its role in regulating telomere length, connection with the inflammatory response, cellular proliferation and vascular growth factors, telomerase has been shown to contribute to cellular transformation, inflammation, epithelial-mesenchymal transition (EMT) and angiogenesis. Due to these apparent connections with cellular proliferation and transformation, conventional wisdom has characterized TERT as an oncogene. Interestingly, recent evidence has emerged which presents a revolutionary therapeutic nature of telomerase in regard to preserving mitochondrial function as well as maintaining endothelial integrity through restoration of nitric oxide-mediated vasodilation and preserving endothelial function. This interconnectedness suggests the therapeutic nature of telomerase in relation to maintaining cardiovascular integrity. Specifically, telomerase has been shown to ameliorate excess ROS production, regulate metabolism, maintain conventional apoptotic function and preserve mtDNA integrity. Each beneficial component relates directly to various types of chemotherapeutic agents, which have been shown to be characterized by and include such damage, therefore proposing a role of telomerase to counter chemotherapeutic-derived cardiovascular dysfunction.
Figure 3
Figure 3
Proposed association between chemotherapeutic-induced apoptosis and oxidative stress elevation. Numerous types of chemotherapeutics such as anthracyclines, alkylating agents, platinum coordination complexes, epi-podophyllotoxins and camptothecins are known to contribute to increased apoptosis. This increased apoptosis has been shown to lead directly to an increase in oxidative stress. Release of cytochrome c encompasses a pathway that leads to apoptosis-induced oxidative stress. Cytochrome c release diverts electrons away from the electron transport system via NADH dehydrogenase and reduced coenzyme Q10, ultimately forming superoxide radicals. Additionally, lipid peroxidation products as well as the subsequent reduction of antioxidants (vitamin E, vitamin C, β-carotene) leads to oxidative stress elevation due to a reduction of the radical capturing ability of blood plasma as well as a diminution of tissue glutathione levels. Interestingly, although apoptosis leads to an increase in oxidative stress, elevated levels of oxidative stress are also shown to contribute to further apoptosis. Endoplasmic reticulum activation as well as a reduction of mitochondrial membrane potential due to elevated levels of superoxide is shown to reduce ATP content and ultimately contribute to an increased risk for apoptosis.
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