Endothelial TERT drives microvascular phenotype associated with coronary artery disease
Erin C. Birch; Yoshinori Nishijima; Shelby N. Hader; Andreas M. Beyer
Microvascular endothelial dysfunction is a powerful predictor of future atherosclerotic cardiac events. Our previous studies revealed that under pathological states, such as coronary artery disease (CAD), the dilation mechanism switches from nitric oxide (NO)-mediated [determined by NO synthase (NOS) inhibitor] to mitochondria-derived H2O2 (determined by H2O2 scavenger). Telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, plays a noncanonical role in preventing the increase of mitochondrial reactive oxygen species in arterioles from subjects with CAD. Activation of TERT can reverse the mechanism of flow-induced, endothelium-dependent dilation from H2O2 to NO. Previous studies showed that systemic TERT knockout (KO) mice reduced NO synthase (NOS)-mediated dilation, accompanied by increased release of flow-induced mitochondrial H2O2 in microcirculations.
In this study, we tested the hypothesis that knocking out the endothelial cell (EC)-specific TERT is sufficient to cause endothelial dysfunction in mice. The third/fourth branch of mesenteric arteries from male EC-specific TERT KO mice (3–5-mo old) were isolated, and endothelial-dependent vasodilator response to flow (FMD) and acetylcholine (ACh) was assessed by videomyography.
In control animals, FMD was mediated by NOS, whereas in EC-TERT KO mice, dilation was significantly reduced, and the remaining dilation was mediated by both NOS and H2O2, suggesting a switch from NO to H2O2-mediated dilation. Similarly, ACh-induced dilation was reduced in EC-TERT KO mice compared with control mice, whereas smooth-muscle-dependent dilation to papaverine was not impaired.
In conclusion, knocking down EC-TERT is sufficient to cause endothelial dysfunction and triggers a switch from physiological NO-mediated dilation to pathological H2O2-mediated dilation.
NEW & NOTEWORTHY
Previously established by Ait-Aissa et al. (Ait-Aissa K, Kadlec AO, Hockenberry J, Gutterman DD, Beyer AM. Am J Physiol Heart Circ Physiol 314: H1053–H1060, 2018), systemic TERT KO mice have a loss of NO synthase-mediated dilation to flow, accompanied by compensatory increased release of flow-induced H2O2 in coronary and peripheral microcirculations.
Our study demonstrates that mice with EC-specific TERT KO exhibit phenotypes similar to systemic TERT deficiency and microvascular pathologies observed in patients with CAD.
These findings underscore the critical, noncanonical, and likely mitochondrial-mediated regulation of vascular tone and systemic cardio-metabolic changes.
Link | PDF | American Journal of Physiology-Heart and Circulatory Physiology [Open Access]
Erin C. Birch; Yoshinori Nishijima; Shelby N. Hader; Andreas M. Beyer
Microvascular endothelial dysfunction is a powerful predictor of future atherosclerotic cardiac events. Our previous studies revealed that under pathological states, such as coronary artery disease (CAD), the dilation mechanism switches from nitric oxide (NO)-mediated [determined by NO synthase (NOS) inhibitor] to mitochondria-derived H2O2 (determined by H2O2 scavenger). Telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, plays a noncanonical role in preventing the increase of mitochondrial reactive oxygen species in arterioles from subjects with CAD. Activation of TERT can reverse the mechanism of flow-induced, endothelium-dependent dilation from H2O2 to NO. Previous studies showed that systemic TERT knockout (KO) mice reduced NO synthase (NOS)-mediated dilation, accompanied by increased release of flow-induced mitochondrial H2O2 in microcirculations.
In this study, we tested the hypothesis that knocking out the endothelial cell (EC)-specific TERT is sufficient to cause endothelial dysfunction in mice. The third/fourth branch of mesenteric arteries from male EC-specific TERT KO mice (3–5-mo old) were isolated, and endothelial-dependent vasodilator response to flow (FMD) and acetylcholine (ACh) was assessed by videomyography.
In control animals, FMD was mediated by NOS, whereas in EC-TERT KO mice, dilation was significantly reduced, and the remaining dilation was mediated by both NOS and H2O2, suggesting a switch from NO to H2O2-mediated dilation. Similarly, ACh-induced dilation was reduced in EC-TERT KO mice compared with control mice, whereas smooth-muscle-dependent dilation to papaverine was not impaired.
In conclusion, knocking down EC-TERT is sufficient to cause endothelial dysfunction and triggers a switch from physiological NO-mediated dilation to pathological H2O2-mediated dilation.
NEW & NOTEWORTHY
Previously established by Ait-Aissa et al. (Ait-Aissa K, Kadlec AO, Hockenberry J, Gutterman DD, Beyer AM. Am J Physiol Heart Circ Physiol 314: H1053–H1060, 2018), systemic TERT KO mice have a loss of NO synthase-mediated dilation to flow, accompanied by compensatory increased release of flow-induced H2O2 in coronary and peripheral microcirculations.
Our study demonstrates that mice with EC-specific TERT KO exhibit phenotypes similar to systemic TERT deficiency and microvascular pathologies observed in patients with CAD.
These findings underscore the critical, noncanonical, and likely mitochondrial-mediated regulation of vascular tone and systemic cardio-metabolic changes.
Link | PDF | American Journal of Physiology-Heart and Circulatory Physiology [Open Access]