Seeding drug discovery: Telomeric tankyrase as a pharmacological target for the pathophysiology of high-altitude hypoxia.

Cellular exposure to extreme environments leads to the expression of multiple proteins that participate in pathophysiological manifestations. Hypobaric hypoxia at high altitude (HA) generates reactive oxygen species (ROS) that can damage telomeres. Tankyrase (TNKS) belongs to multiple telomeric protein complexes and is actively involved in DNA damage repair. Although published research on TNKS indicates its possible role in cancer and other hypoxic diseases, its role in HA sicknesses remains elusive. Understanding the roles of telomeres, telomerase, and TNKS could ameliorate physiological issues experienced at HA. In addition, telomeric TNKS could be a potential biomarker in hypoxia-induced sicknesses or acclimatization. Thus, a new research avenue on TNKS linked to HA sickness might lead to the discovery of drugs for hypobaric hypoxia.

Telomere length in young patients with acute myocardial infarction without conventional risk factors: A pilot study from a South Asian population.

BACKGROUND: There is need to identify novel markers that lead to an early occurrence of myocardial infarction (MI) in young South Asian population. This population has different risk profile as compared with others. Telomere length is known to be a marker of aging, and shorter telomeres have been reported in cardiovascular diseases (CVDs). We aimed to identify the association of telomere length in young nonsmokers and non-diabetic MI patients. METHODS: In a case-control study of 154 subjects (n = 77 cases (ages 18-45 years, non-diabetic, non-smoker patients with MI) and n = 77, age and sex matched healthy controls), DNA extraction from peripheral blood leukocytes was carried out and the relative telomere length was estimated by quantitative PCR. The results were adjusted with various demographic parameters like age, gender and body mass index (BMI). The correlation studies were carried out between telomere length, sex and type of MI. RESULTS: The relative telomere length was significantly shorter in young MI patients (31-45 years) compared with matched healthy controls (p < 0.0001). Interestingly, in a gender-based comparison, the female patients had shorter telomere length (p < 0.01). CONCLUSION: In this pilot study, we found that the telomere length was shorter among young, non-diabetic, non-smoker MI patients as compared with similar young controls without MI in a South Asian cohort. Thus, telomere length may be a potential screening tool for young patients who don't have conventional risk factors. Larger studies are needed to confirm these findings.

Shorter telomere length, higher telomerase activity in association with tankyrase gene polymorphism contribute to high-altitude pulmonary edema.

High-altitude pulmonary edema (HAPE) is a noncardiogenic form of pulmonary edema, which is induced upon exposure to hypobaric hypoxia at high altitude (HA). Hypobaric hypoxia generates reactive oxygen species that may damage telomeres and disturb normal physiological processes. Telomere complex comprises of multiple proteins, of which, tankyrase (TNKS) is actively involved in DNA damage repairs. We hence investigated the association of TNKS and telomeres with HAPE to delineate their potential role at HA. The study was performed in three groups, High-altitude pulmonary edema patients (HAPE-p, n = 200), HAPE-resistant sojourners (HAPE-r, n = 200) and highland permanent healthy residents (HLs, n = 200). Variants of TNKS were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Plasma TNKS level was estimated using enzyme-linked immunosorbent assay, expression of TNKS and relative telomere length were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and telomerase activity was assessed by the telomere repeat amplification protocol assay. TNKS poly-ADP ribosylates the telomere-repeat factor (TRF), which is a negative regulator of telomere length. Consequently, TRF expression was also measured by RT-qPCR. The TNKS heterozygotes rs7015700GA were prevalent in HLs compared to the HAPE-p and HAPE-r. The plasma TNKS was significantly decreased in HAPE-p than HAPE-r (P = 0.006). TNKS was upregulated 9.27 folds in HAPE-p (P = 1.01E-06) and downregulated in HLs by 3.3 folds (P = 0.02). The telomere length was shorter in HAPE-p compared to HAPE-r (P = 0.03) and HLs (P = 4.25E-4). The telomerase activity was significantly higher in HAPE-p compared to both HAPE-r (P = 0.01) and HLs (P = 0.001). HAPE-p had the lowest TNKS levels (0.186 ± 0.031 ng/µl) and the highest telomerase activity (0.0268 amoles/µl). The findings of the study indicate the association of TNKS and telomeres with HA adaptation/maladaptation.