The role of telomerase reverse transcriptase in the mitochondrial protective functions of Angiotensin-(1-7) in diabetic CD34+ cells.

Angiotensin (Ang)-(1-7) stimulates vasoprotective functions of diabetic (DB) CD34+ hematopoietic stem/progenitor cells partly by decreasing reactive oxygen species (ROS), increasing nitric oxide (NO) levels and decreasing TGFß1 secretion. Telomerase reverse transcriptase (TERT) translocates to mitochondria and regulates ROS generation. Alternative splicing of TERT results in variants α-, ß- and α-ß-TERT, which may oppose functions of full-length (FL) TERT. This study tested if the protective functions of Ang-(1-7) or TGFß1-silencing are mediated by mitoTERT and that diabetes decreases FL-TERT expression by inducing splicing. CD34+ cells were isolated from the peripheral blood mononuclear cells of nondiabetic (ND, n = 68) or DB (n = 74) subjects. NO and mitoROS levels were evaluated by flow cytometry. TERT splice variants and mitoDNA-lesions were characterized by qPCR. TRAP assay was used for telomerase activity. Decoy peptide was used to block mitochondrial translocation (mitoXTERT). TERT inhibitor or mitoXTERT prevented the effects of Ang-(1-7) on NO or mitoROS levels in DB-CD34+ cells. FL-TERT expression and telomerase activity were lower and mitoDNA-lesions were higher in DB cells compared to ND and were reversed by Ang-(1-7) or TGFß1-silencing. The prevalence of TERT splice variants, with predominant ß-TERT expression, was higher and the expression of FL-TERT was lower in DB cells (n = 25) compared to ND (n = 30). Ang-(1-7) or TGFß1-silencing decreased TERT-splicing and increased FL-TERT. Blocking of ß-splicing increased FL-TERT and protected mitoDNA in DB-cells. The findings suggest that diabetes induces TERT-splicing in CD34+ cells and that ß-TERT splice variant largely contributes to the mitoDNA oxidative damage.

Disparities in Cardiovascular Disease-Related Outcomes Among Cancer Survivors in the United States: A Systematic Review of the Literature.

BACKGROUND: Cancer and cardiovascular disease (CVD) are major causes of morbidity and mortality in the United States (US). Cancer survivors have increased risks for CVD and CVD-related mortality due to multiple factors including cancer treatment-related cardiotoxicity. Disparities are rooted in differential exposure to risk factors and social determinants of health (SDOH), including systemic racism. This review aimed to assess SDOH's role in disparities, document CVD-related disparities among US cancer survivors, and identify literature gaps for future research. METHODS: Following the Peer Review of Electronic Search Strategies (PRESS) guidelines, MEDLINE, PsycINFO, and Scopus were searched on March 15, 2021, with an update conducted on September 26, 2023. Articles screening was performed using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, a pre-defined Population, Exposure, Comparison, Outcomes, and Settings (PECOS) framework, and the Rayyan platform. A modified version of the Newcastle-Ottawa Scale was used to assess the risk of bias, and RAW Graphs for alluvial charts. This review is registered with PROSPERO under ID #CRD42021236460. RESULTS: Out of 7,719 retrieved articles, 24 were included, and discussed diverse SDOH that contribute to CVD-related disparities among cancer survivors. The 24 included studies had a large combined total sample size (n=7,704,645; median=19,707). While various disparities have been investigated, including rural-urban, sex, socioeconomic status, and age, a notable observation is that non-Hispanic Black cancer survivors experience disproportionately adverse CVD outcomes when compared to non-Hispanic White survivors. This underscores historical racism and discrimination against non-Hispanic Black individuals as fundamental drivers of CVD-related disparities. CONCLUSIONS: Stakeholders should work to eliminate the root causes of disparities. Clinicians should increase screening for risk factors that exacerbate CVD-related disparities among cancer survivors. Researchers should prioritise the investigation of systemic factors driving disparities in cancer and CVD and develop innovative interventions to mitigate risk in cancer survivors.

The impact of greenspace or nature-based interventions on cardiovascular health or cancer-related outcomes: A systematic review of experimental studies.

SIGNIFICANCE: Globally, cardiovascular disease (CVD) and cancer are leading causes of morbidity and mortality. While having different etiologies, CVD and cancer are linked by multiple shared risk factors, the presence of which exacerbate adverse outcomes for individuals with either disease. For both pathologies, factors such as poverty, lack of physical activity (PA), poor dietary intake, and climate change increase risk of adverse outcomes. Prior research has shown that greenspaces and other nature-based interventions (NBIs) contribute to improved health outcomes and climate change resilience. OBJECTIVE: To summarize evidence on the impact of greenspaces or NBIs on cardiovascular health and/or cancer-related outcomes and identify knowledge gaps to inform future research. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and Peer Review of Electronic Search Strategies (PRESS) guidelines, we searched five databases: Web of Science, Scopus, Medline, PsycINFO and GreenFile. Two blinded reviewers used Rayyan AI and a predefined criteria for article inclusion and exclusion. The risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale (NOS). This review is registered with PROSPERO, ID # CRD42021231619. RESULTS & DISCUSSION: Of 2565 articles retrieved, 31 articles met the inclusion criteria, and overall had a low risk of bias. 26 articles studied cardiovascular related outcomes and 5 studied cancer-related outcomes. Interventions were coded into 4 categories: forest bathing, green exercise, gardening, and nature viewing. Outcomes included blood pressure (BP), cancer-related quality of life (QoL) and (more infrequently) biomarkers of CVD risk. Descriptions of findings are presented as well as visual presentations of trends across the findings using RAW graphs. Overall studies included have a low risk of bias; and alluvial chart trends indicated that NBIs may have beneficial effects on CVD and cancer-related outcomes. CONCLUSIONS & IMPLICATIONS: (1) Clinical implication: Healthcare providers should consider the promotion of nature-based programs to improve health outcomes. (2) Policy implication: There is a need for investment in equitable greenspaces to improve health outcomes and build climate resilient neighborhoods. (3) Research or academic implication: Research partnerships with community-based organizations for a comprehensive study of benefits associated with NBIs should be encouraged to reduce health disparities and ensure intergenerational health equity. There is a need for investigation of the mechanisms by which NBIs impact CVD and exploration of the role of CVD biological markers of inflammation among cancer survivors.

Emerging mitochondrial signaling mechanisms in cardio-oncology: beyond oxidative stress.

Many anticancer therapies (CTx) have cardiotoxic side effects that limit their therapeutic potential and cause long-term cardiovascular complications in cancer survivors. This has given rise to the field of cardio-oncology, which recognizes the need for basic, translational, and clinical research focused on understanding the complex signaling events that drive CTx-induced cardiovascular toxicity. Several CTx agents cause mitochondrial damage in the form of mitochondrial DNA deletions, mutations, and suppression of respiratory function and ATP production. In this review, we provide a brief overview of the cardiovascular complications of clinically used CTx agents and discuss current knowledge of local and systemic secondary signaling events that arise in response to mitochondrial stress/damage. Mitochondrial oxidative stress has long been recognized as a contributor to CTx-induced cardiotoxicity; thus, we focus on emerging roles for mitochondria in epigenetic regulation, innate immunity, and signaling via noncoding RNAs and mitochondrial hormones. Because data exploring mitochondrial secondary signaling in the context of cardio-oncology are limited, we also draw upon clinical and preclinical studies, which have examined these pathways in other relevant pathologies.

Greenspace, Inflammation, Cardiovascular Health, and Cancer: A Review and Conceptual Framework for Greenspace in Cardio-Oncology Research.

Cardiovascular disease (CVD) is a leading cause of global morbidity and mortality. Cancer survivors have significantly elevated risk of poor cardiovascular (CV) health outcomes due to close co-morbid linkages and shared risk factors between CVD and cancer, as well as adverse effects of cancer treatment-related cardiotoxicity. CVD and cancer-related outcomes are exacerbated by increased risk of inflammation. Results from different pharmacological interventions aimed at reducing inflammation and risk of major adverse cardiovascular events (MACEs) have been largely mixed to date. Greenspaces have been shown to reduce inflammation and have been associated with CV health benefits, including reduced CVD behavioral risk factors and overall improvement in CV outcomes. Greenspace may, thus, serve to alleviate the CVD burden among cancer survivors. To understand pathways through which greenspace can prevent or reduce adverse CV outcomes among cancer survivors, we review the state of knowledge on associations among inflammation, CVD, cancer, and existing pharmacological interventions. We then discuss greenspace benefits for CV health from ecological to multilevel studies and a few existing experimental studies. Furthermore, we review the relationship between greenspace and inflammation, and we highlight forest bathing in Asian-based studies while presenting existing research gaps in the US literature. Then, we use the socioecological model of health to present an expanded conceptual framework to help fill this US literature gap. Lastly, we present a way forward, including implications for translational science and a brief discussion on necessities for virtual nature and/or exposure to nature images due to the increasing human-nature disconnect; we also offer guidance for greenspace research in cardio-oncology to improve CV health outcomes among cancer survivors.

Endothelial dysfunction as a complication of anti-cancer therapy.

Recent strides in anti-cancer therapeutics have improved longevity and led to a growing population of cancer survivors, who are increasingly likely to die of other causes. Treatment-induced cardiotoxicity is a complication of several therapeutic agents with acute and long-term consequences for cancer patients. Vascular endothelial dysfunction is a precursor and hallmark of ischemic coronary disease and may play a role in anti-cancer therapy-induced cardiotoxicity. This review summarizes clinical evidence for endothelial dysfunction following anti-cancer therapy and extends the discussion to include the impact of therapeutic agents on conduit arteries and the microcirculation. We highlight the role of innate immune system activation and cross-talk between inflammation and oxidative stress as pathogenic mechanisms underlying anti-cancer therapy-induced vascular toxicity. Understanding the impact of anti-cancer agents on the vascular endothelium will inform therapeutic approaches to prevent or reverse treatment-induced cardiotoxicity and may serve as an important tool to predict, monitor, and prevent adverse cardiovascular outcomes in patients undergoing treatment.

Autophagy, TERT, and mitochondrial dysfunction in hyperoxia.

Ventilation with gases containing enhanced fractions of oxygen is the cornerstone of therapy for patients with hypoxia and acute respiratory distress syndrome. Yet, hyperoxia treatment increases free reactive oxygen species (ROS)-induced lung injury, which is reported to disrupt autophagy/mitophagy. Altered extranuclear activity of the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), plays a protective role in ROS injury and autophagy in the systemic and coronary endothelium. We investigated interactions between autophagy/mitophagy and TERT that contribute to mitochondrial dysfunction and pulmonary injury in cultured rat lung microvascular endothelial cells (RLMVECs) exposed in vitro, and rat lungs exposed in vivo to hyperoxia for 48 h. Hyperoxia-induced mitochondrial damage in rat lungs [TOMM20, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)], which was paralleled by increased markers of inflammation [myeloperoxidase (MPO), IL-1ß, TLR9], impaired autophagy signaling (Beclin-1, LC3B-II/1, and p62), and decreased the expression of TERT. Mitochondrial-specific autophagy (mitophagy) was not altered, as hyperoxia increased expression of Pink1 but not Parkin. Hyperoxia-induced mitochondrial damage (TOMM20) was more pronounced in rats that lack the catalytic subunit of TERT and resulted in a reduction in cellular proliferation rather than cell death in RLMVECs. Activation of TERT or autophagy individually offset mitochondrial damage (MTT). Combined activation/inhibition failed to alleviate hyperoxic-induced mitochondrial damage in vitro, whereas activation of autophagy in vivo decreased mitochondrial damage (MTT) in both wild type (WT) and rats lacking TERT. Functionally, activation of either TERT or autophagy preserved transendothelial membrane resistance. Altogether, these observations show that activation of autophagy/mitophagy and/or TERT mitigate loss of mitochondrial function and barrier integrity in hyperoxia.NEW & NOTEWORTHY In cultured pulmonary artery endothelial cells and in lungs exposed in vivo to hyperoxia, autophagy is activated, but clearance of autophagosomes is impaired in a manner that suggests cross talk between TERT and autophagy. Stimulation of autophagy prevents hyperoxia-induced decreases in mitochondrial metabolism and sustains monolayer resistance. Hyperoxia increases mitochondrial outer membrane (TOMM20) protein, decreases mitochondrial function, and reduces cellular proliferation without increasing cell death.

Preclinical Models of Cancer Therapy-Associated Cardiovascular Toxicity: A Scientific Statement From the American Heart Association.

Although cardiovascular toxicity from traditional chemotherapies has been well recognized for decades, the recent explosion of effective novel targeted cancer therapies with cardiovascular sequelae has driven the emergence of cardio-oncology as a new clinical and research field. Cardiovascular toxicity associated with cancer therapy can manifest as a broad range of potentially life-threatening complications, including heart failure, arrhythmia, myocarditis, and vascular events. Beyond toxicology, the intersection of cancer and heart disease has blossomed to include discovery of genetic and environmental risk factors that predispose to both. There is a pressing need to understand the underlying molecular mechanisms of cardiovascular toxicity to improve outcomes in patients with cancer. Preclinical cardiovascular models, ranging from cellular assays to large animals, serve as the foundation for mechanistic studies, with the ultimate goal of identifying biologically sound biomarkers and cardioprotective therapies that allow the optimal use of cancer treatments while minimizing toxicities. Given that novel cancer therapies target specific pathways integral to normal cardiovascular homeostasis, a better mechanistic understanding of toxicity may provide insights into fundamental pathways that lead to cardiovascular disease when dysregulated. The goal of this scientific statement is to summarize the strengths and weaknesses of preclinical models of cancer therapy-associated cardiovascular toxicity, to highlight overlapping mechanisms driving cancer and cardiovascular disease, and to discuss opportunities to leverage cardio-oncology models to address important mechanistic questions relevant to all patients with cardiovascular disease, including those with and without cancer.

BCR-ABL tyrosine kinase inhibitors promote pathological changes in dilator phenotype in the human microvasculature.

OBJECTIVE: Treatment with BCR-ABL tyrosine kinase inhibitors (TKIs) is the standard of care for patients with chronic myeloid leukemia, however evidence indicates these compounds may have cardiovascular side-effects. This study sought to determine if ex vivo exposure of human adipose arterioles to the BCR-ABL TKIs imatinib and nilotinib causes endothelial dysfunction. METHODS: Human adipose arterioles were incubated overnight in cell culture media containing vehicle (PBS), imatinib (10 µmol/L) or nilotinib (100 µmol/L). Arterioles were cannulated onto glass pipettes and flow mediated dilation (FMD) was assessed via video microscopy. To determine the mechanism of vasodilation, FMD was re-assessed in the presence of either the nitric oxide synthase inhibitor L-NAME (100 µmol/L) or the H2 O2 scavenger PEG-Catalase (500 U/mL). RESULTS: Neither imatinib nor nilotinib affected the magnitude of FMD (max dilation = 78±17% vehicle, 80 ± 24% nilotinib, 73 ± 13% imatinib). FMD was decreased by L-NAME in vehicle-treated arterioles (max dilation = 47±29%). Conversely, L-NAME had no effect on FMD in imatinib- or nilotinib-treated vessels (max dilation = 79±14% and 80 ± 24%, respectively), rather FMD was inhibited by PEG-Catalase (max dilation = 29±11% and 29 ± 14%, respectively). CONCLUSION: Incubating human arterioles with imatinib or nilotinib switches the mediator of FMD from vasoprotective nitric oxide to pro-inflammatory H2 O2 .

Detrimental effects of chemotherapy on human coronary microvascular function.

Chemotherapy (CT) is a necessary treatment to prevent the growth and survival of cancer cells. However, CT has a well-established adverse impact on the cardiovascular (CV) system, even years after cessation of treatment. The effects of CT drugs on tumor vasculature have been the focus of much research, but little evidence exists showing the effects on the host microcirculation. Microvascular (MV) dysfunction is an early indicator of numerous CV disease phenotypes, including heart failure. The goal of this study was to evaluate the direct effect of doxorubicin (Dox) on human coronary MV function. To study the effect of CT on the cardiac MV function, flow-mediated dilation (FMD), pharmacologically-induced endothelial dependent dilation to acetylcholine (ACh), and smooth muscle-dependent dilation to papaverine were investigated. Vessels were freshly isolated from atrial appendages of adult patients undergoing cardiopulmonary bypass surgery or from cardiac tissue of pediatric patients, collected at the time of surgery to repair congenital heart defects. Isolated vessels were incubated in endothelial culture medium containing vehicle or Dox (100 nm, 15-20 h) and used to measure dilator function by video microscopy. Ex vivo treatment of adult human coronary microvessels with Dox significantly impaired flow-mediated dilation (FMD). Conversely, in pediatric coronary microvessels, Dox-induced impairment of FMD was significantly reduced in comparison with adult subjects. In both adult and pediatric coronary microvessels, ACh-induced constriction was reversed into dilation in the presence of Dox. Smooth muscle-dependent dilation remained unchanged in all groups tested. In vessels from adult subjects, acute treatment with Dox in clinically relevant doses caused significant impairment of coronary arteriolar function, whereas vessels from pediatric subjects showed only marginal impairment to the same stressor. This interesting finding might explain the delayed onset of future adverse CV events in children compared with adults after anthracycline therapy.NEW & NOTEWORTHY We have characterized, for the first time, human microvascular responses to acute ex vivo exposure to doxorubicin in coronary vessels from patients without cancer. Our data show an augmented impairment of endothelial function in vessels from adult subjects compared with pediatric samples.

Cancer therapy-induced cardiovascular toxicity: old/new problems and old drugs.

Cardio-oncology has emerged as an exciting new field at the intersection of cardiology and oncology. While improved oncology treatment efficacy has increased survival rates in cancer patients, the long-term cardiovascular consequences of this life-saving treatment have become more clinically relevant. Both traditional and newer (targeted) cancer therapies can have cardiovascular and metabolic sequelae, resulting in heart failure, coronary artery disease, myocarditis, pericardial disease, hypertension, and vascular and metabolic perturbations (Moslehi JJ. Cardiovascular toxic effects of targeted cancer therapies. N Engl J Med 375: 1457-1467, 2016). Both acute and chronic cardiovascular toxicities have proven challenging for clinicians and patients, significantly contributing to morbidity and mortality. Although chronic cardiovascular disease affects a growing number of cancer survivors (~17 million in the United States in 2019), cardiovascular toxicities associated with cancer and cancer therapies are poorly understood mechanistically. To balance potential damage to the cardiovascular system with effective and efficient cancer treatment, novel strategies are sorely needed. This perspective focuses on an assembly of articles that discuss novel means of counteracting adverse cardiovascular events in response to anticancer therapy. In light of new clinical syndromes in cardiology due to cancer therapies, we hope to highlight promising research opportunities offered by cardio-oncology (Bellinger AM, Arteaga CL, Force T, Humphreys BD, Demetri GD, Druker BJ, Moslehi JJ. Cardio-oncology: how new targeted cancer therapies and precision medicine can inform cardiovascular discovery. Circulation 132: 2248-2258, 2015.).

Mitochondrial Oxidative Phosphorylation defect in the Heart of Subjects with Coronary Artery Disease.

Coronary artery disease (CAD) is a leading cause of death worldwide and frequently associated with mitochondrial dysfunction. Detailed understanding of abnormalities in mitochondrial function that occur in patients with CAD is lacking. We evaluated mitochondrial damage, energy production, and mitochondrial complex activity in human non-CAD and CAD hearts. Fresh and frozen human heart tissue was used. Cell lysate or mitochondria were isolated using standard techniques. Mitochondrial DNA (mtDNA), NAD + and ATP levels, and mitochondrial oxidative phosphorylation capacity were evaluated. Proteins critical to the regulation of mitochondrial metabolism and function were also evaluated in tissue lysates. PCR analysis revealed an increase in mtDNA lesions and the frequency of mitochondrial common deletion, both established markers for impaired mitochondrial integrity in CAD compared to non-CAD patient samples. NAD+ and ATP levels were significantly decreased in CAD subjects compared to Non-CAD (NAD+ fold change: non-CAD 1.00 ± 0.17 vs. CAD 0.32 ± 0.12* and ATP fold change: non-CAD 1.00 ± 0.294 vs. CAD 0.01 ± 0.001*; N = 15, P < 0.005). We observed decreased respiration control index in CAD tissue and decreased activity of complexes I, II, and III. Expression of ETC complex subunits and respirasome formation were increased; however, elevations in the de-active form of complex I were observed in CAD. We observed a corresponding increase in glycolytic flux, indicated by a rise in pyruvate kinase and lactate dehydrogenase activity, indicating a compensatory increase in glycolysis for cellular energetics. Together, these results indicate a shift in mitochondrial metabolism from oxidative phosphorylation to glycolysis in human hearts subjects with CAD.

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

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.

Friend or foe? Telomerase as a pharmacological target in cancer and cardiovascular disease.

Aging, cancer, and chronic disease have remained at the forefront of basic biological research for decades. Within this context, significant attention has been paid to the role of telomerase, the enzyme responsible for lengthening telomeres, the nucleotide sequences located at the end of chromosomes found in the nucleus. Alterations in telomere length and telomerase activity are a common denominator to the underlying pathology of these diseases. While nuclear-specific, telomere-lengthening effects of telomerase impact cellular/organismal aging and cancer development, non-canonical, extra-nuclear, and non-telomere-lengthening contributions of telomerase have only recently been described and their exact physiological implications are ill defined. Although the mechanism remains unclear, recent reports reveal that the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), regulates levels of mitochondrial-derived reactive oxygen species (mtROS), independent of its established role in the nucleus. Telomerase inhibition has been the target of chemotherapy (directed or indirectly) for over a decade now, yet no telomerase inhibitor is FDA approved and few are currently in late-stage clinical trials, possibly due to underappreciation of the distinct extra-nuclear functions of telomerase. Moreover, evaluation of telomerase-specific therapies is largely limited to the context of chemotherapy, despite reports of the beneficial effects of telomerase activation in the cardiovascular system in relation to such processes as endothelial dysfunction and myocardial infarction. Thus, there is a need for better understanding of telomerase-focused cell and organism physiology, as well as development of telomerase-specific therapies in relation to cancer and extension of these therapies to cardiovascular pathologies. This review will detail findings related to telomerase and evaluate its potential to serve as a therapeutic target.

Vascular Actions of Angiotensin 1-7 in the Human Microcirculation: Novel Role for Telomerase.

OBJECTIVE: This study examined vascular actions of angiotensin 1-7 (ANG 1-7) in human atrial and adipose arterioles. APPROACH AND RESULTS: The endothelium-derived hyperpolarizing factor of flow-mediated dilation (FMD) switches from antiproliferative nitric oxide (NO) to proatherosclerotic hydrogen peroxide in arterioles from humans with coronary artery disease (CAD). Given the known vasoprotective properties of ANG 1-7, we tested the hypothesis that overnight ANG 1-7 treatment restores the NO component of FMD in arterioles from patients with CAD. Endothelial telomerase activity is essential for preserving the NO component of vasodilation in the human microcirculation; thus, we also tested whether telomerase activity was necessary for ANG 1-7-mediated vasoprotection by treating separate arterioles with ANG 1-7±the telomerase inhibitor 2-[[(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-yl]amino]benzoic acid. ANG 1-7 dilated arterioles from patients without CAD, whereas dilation was significantly reduced in arterioles from patients with CAD. In atrial arterioles from patients with CAD incubated with ANG 1-7 overnight, the NO synthase inhibitor NG-nitro-l-arginine methyl ester abolished FMD, whereas the hydrogen peroxide scavenger polyethylene glycol catalase had no effect. Conversely, in vessels incubated with ANG 1-7+2-[[(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-yl]amino]benzoic acid, NG-nitro-l-arginine methyl ester had no effect on FMD, but polyethylene glycol catalase abolished dilation. In cultured human coronary artery endothelial cells, ANG 1-7 significantly increased telomerase activity. These results indicate that ANG 1-7 dilates human microvessels, and dilation is abrogated in the presence of CAD. Furthermore, ANG 1-7 treatment is sufficient to restore the NO component of FMD in arterioles from patients with CAD in a telomerase-dependent manner. CONCLUSIONS: ANG 1-7 exerts vasoprotection in the human microvasculature via modulation of telomerase activity.

Regulation of the human coronary microcirculation.

Atherosclerosis of conduit epicardial arteries is the principal culprit behind the complications of coronary heart disease, but a growing body of literature indicates that the coronary microcirculation also contributes substantially to the pathophysiology of cardiovascular disease. An understanding of mechanisms regulating microvascular function in humans is an essential foundation for understanding the role in disease, especially since these regulatory mechanisms vary substantially across species and vascular beds. In fact all subjects whose coronary tissue was used in the studies described have medical conditions that warrant cardiac surgery, thus relevance to the normal human must be inferential and is based on tissue from subjects without known arteriosclerotic disease. This review will focus on recent advances in the physiological and pathological mechanisms of coronary microcirculatory control, describing a robust plasticity in maintaining endothelial control over dilation, including mechanisms that are most relevant to the human heart. This article is part of a Special Issue entitled "Coronary Blood Flow".

Inactivation of Bardet-Biedl syndrome genes causes kidney defects.

Bardet-Biedl syndrome (BBS) is a rare hereditary autosomal recessive disease associated with several features including obesity, hypertension, and renal abnormalities. The underlying mechanisms of renal defects associated with BBS remain poorly defined. We examined the histological, molecular, and functional renal changes in BBS mouse models that have features of the human disorder. Interestingly, obese hypertensive Bbs4(-/-) mice exhibited inflammatory infiltration and renal cysts, whereas the obese normotensive Bbs2(-/-) mice had only minor inflammatory infiltration. Accordingly, the expression level of inducible nitric oxide synthase was elevated in the kidney of both BBS mice with a more marked increase in Bbs4(-/-) mice. In contrast, endothelial nitric oxide synthase expression was decreased in Bbs4(-/-), but not Bbs2(-/-), mice. Similarly, the expression levels of transient receptor potential vanilloid 1 and 4 channels as well as ß- and γ-subunits of epithelial Na channel were significantly reduced only in the kidney of Bbs4(-/-) mice. Metabolic studies revealed changes in urine output and urinary concentrations of creatinine, blood urea nitrogen, sodium, and potassium with a more pronounced effect in Bbs4(-/-) mice. Finally, we found that calorie restriction which prevented obesity in BBS mice reversed the morphological and molecular changes found in Bbs2(-/-) and Bbs4(-/-) mice, indicating the kidney abnormalities associated with BBS are obesity related. These findings extend our understanding of the function of BBS proteins and emphasize the importance of these proteins in renal physiology.