Justin Park

 Background: In 50% of patients who undergo angiography due to angina and confirmed ischemia, no significant coronary obstructions are found.¹ This finding has been termed ischemia with no obstructive coronary arteries (INOCA). Around 41% of INOCA patients have coronary microvascular disease (CMD).² CMD is also present along with various other heart diseases, including coronary artery disease (CAD).³ CMD is a subset of ischemic heart disease characterized by dysfunction in the control of arteriolar tone, impairing coronary blood flow.³ Although the mechanism is unclear, endothelial dysfunction appears to be the driving factor.⁴ Endothelial dysfunction, with increased mitochondrial reactive oxygen species (_mtROS), disrupts nitric oxide (NO) release and promotes a shift from NO- to hydrogen peroxide (H₂O₂)-mediated vasodilation. No CMD-specific treatment options are available.³ Telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, has the ability to localize to the nucleus and mitochondrion.⁵ Its activity has been linked to decreased _mtROS levels and increased cardioprotection and endothelial NO synthase activation.^6,7 These findings show TERT’s potential key role in the development of CMD.

Objective: In this literature review, the effects of TERT on vasodilator function of coronary microvessels was investigated.

Search Methods: An online search in PubMed was done from 2018 to 2024 with these keywords: “telomerase reverse transcriptase”, “coronary microvascular disease”, “NO-mediated vasodilation”, “H₂O₂-mediated vasodilation”, and “endothelial dysfunction”.

Results: One study showed that knocking out TERT has no effect on vasodilator function in coronary arterioles of mice.⁸ However, knocking out TERT appears to affect the mechanism of vasodilation. Keeping TERT intact promoted NO-mediated vasodilation, while knocking out TERT resulted in the pathologic shift from NO- to H₂O₂-mediated vasodilation. Another study found higher levels of β-deletion TERT in human coronary arterioles affected by CAD compared to those not affected by CAD.⁴ β-deletion TERT is a common wildtype mutation that inhibits TERT’s catalytic function. The study also found higher levels of full-length TERT in non-CAD vessels than CAD vessels. The CAD and non-CAD vessels dilated in response to H₂O₂ and NO, respectively. Inhibiting TERT’s mitochondrial localization through gene editing caused the pathologic shift from NO- to H₂O₂-mediated vasodilation in non-CAD vessels and had no significant effects on CAD vessels. Inhibiting TERT’s nuclear localization through gene editing had no significant effects on non-CAD vessels and restored NO-mediated vasodilation in CAD vessels. These vessels were also treated with mimetic peptides that inhibit post-transcriptional modification of TERT and thus, nuclear or mitochondrial import. These potential therapeutic agents exhibited similar effects to inhibition of subcellular localization through gene editing.

Conclusion: TERT function, specifically in the mitochondrion, is essential for

maintaining physiologic NO-mediated vasodilation of coronary microvessels.⁴ Enhancing TERT’s mitochondrial function can reverse the phenotypic changes seen with endothelial dysfunction in coronary arterioles. Thus, mitochondrial TERT has emerged as a potential treatment target for CMD. More studies need to be done to confirm the therapeutic effects of mitochondrial TERT. Furthermore, how TERT preserves NO-mediated vasodilation is unknown. Investigating TERT’s interaction with autophagy may elucidate this unknown.⁹

Works Cited:

1. Mehta PK, Huang J, Levit RD, Malas W, Waheed N, Bairey Merz CN. Ischemia and No Obstructive Coronary Arteries (INOCA): A Narrative Review. Atherosclerosis. 2022;363:8-21. doi:10.1016/j.atherosclerosis.2022.11.009
2. Mileva N, Nagumo S, Mizukami T, et al. Prevalence of Coronary Microvascular Disease and Coronary Vasospasm in Patients with Nonobstructive Coronary Artery Disease: Systematic Review and Meta-Analysis. J Am Heart Assoc. 2022;11(7):e023207. doi:10.1161/JAHA.121.023207
3. Taqueti VR, Di Carli MF. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018;72(21):2625-2641. doi:10.1016/j.jacc.2018.09.042
4. Ait-Aissa K, Norwood-Toro LE, Terwoord J, et al. Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment with Implications for Coronary Artery Disease. Function (Oxf). 2022;3(5):zqac043. doi:10.1093/function/zqac043
5. Hoffmann J, Richardson G, Haendeler J, Altschmied J, Andrés V, Spyridopoulos I. Telomerase as a Therapeutic Target in Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2021;41(3):1047-1061. doi:10.1161/ATVBAHA.120.315695
6. Ait-Aissa K, Heisner JS, Norwood Toro LE, et al. Telomerase Deficiency Predisposes to Heart Failure and Ischemia-Reperfusion Injury. Front Cardiovasc Med. 2019;6:31. doi:10.3389/fcvm.2019.00031
7. Ale-Agha N, Jakobs P, Goy C, et al. Mitochondrial Telomerase Reverse Transcriptase Protects from Myocardial Ischemia/Reperfusion Injury by Improving Complex I Composition and Function. Circulation. 2021;144(23):1876-1890. doi:10.1161/CIRCULATIONAHA.120.051923
8. Ait-Aissa K, Kadlec AO, Hockenberry J, Gutterman DD, Beyer AM. Telomerase Reverse Transcriptase Protects Against Angiotensin II-Induced Microvascular Endothelial Dysfunction. Am J Physiol Heart Circ Physiol. 2018;314(5):H1053-H1060. doi:10.1152/ajpheart.00472.2017
9. Hughes WE, Chabowski DS, Ait-Aissa K, et al. Critical Interaction Between Telomerase and Autophagy in Mediating Flow-Induced Human Arteriolar Vasodilation. Arterioscler Thromb Vasc Biol. 2021;41(1):446-457. doi:10.1161/ATVBAHA.120.314944