Mini-review: Angiotensin- converting enzyme 1 (ACE1) and the impact for diseases such as Alzheimer’s disease, sarcopenia, cancer, and COVID-19

Ageing has been associated with comorbidities, systemic low-grade of inflammation, and immunosenescence. Hypertension is the most common morbidity and anti-hypertensives are used for more than 50%. Angiotensin-converting enzyme 1 inhibitors (ACEi) and angiotensin II receptor blockers (ARB) control blood pressure but also seem to play a role in comorbidities such as Alzheimer’s disease, sarcopenia and cancer. The impact of anti-hypertensives in comorbidities is due to the expression of renin-angiotensin system (RAS) in several tissues and body fluids. Angiotensin-converting enzyme 1 (ACE1) has been linked to oxidative stress, metabolism, and inflammation. The levels and activity of ACE1 are under genetic control and polymorphisms have been correlated with susceptibility to Alzheimer’s disease. In addition, some results found that ACEi and ARB users present delayed cognitive decline and reduced risk of dementia. Regarding to sarcopenia, RAS has been linked to the catabolic and anabolic pathways for muscle mass maintenance. In some studies, older adults using ACEi were highly benefited by exercise training. In cancer, RAS and its products have been shown to play a role since their inhibition in animal models modulates tumor microenvironment and improves the delivery of chemotherapy drugs. Clinically, the incidence of colorectal cancer is reduced in patients using ACEi and ARB. During the pandemic COVID-19 it was found that ACE2 receptor plays a role in the entry of SARS-CoV-2 into the host cell. ACE1 genotypes have been linked to an increased risk for COVID-19 and severe disease. In some studies COVID-19 patients taking ARB or ACEi presented better outcome.

[1]  Zhongshang Yuan,et al.  Multi-trajectories of systolic and diastolic hypertension and coronary heart disease in middle-aged and older adults , 2022, Frontiers in Public Health.

[2]  Yaritza Inostroza-Nieves,et al.  Renin-angiotensin-system increases phosphorylated tau and Reactive Oxygen Species in human cortical neuron cell line , 2022, Biochemistry and biophysics reports.

[3]  I. Banerjee,et al.  Systematic review and meta-analysis of human genetic variants contributing to COVID-19 susceptibility and severity , 2022, Gene.

[4]  D. Frasca,et al.  Angiotensin converting enzyme (ACE) expression in leukocytes of older adults , 2022, medRxiv.

[5]  C. Leitão,et al.  Genetic polymorphisms associated with susceptibility to COVID-19 disease and severity: A systematic review and meta-analysis , 2022, PloS one.

[6]  O. Nedić,et al.  The association of ACE1, ACE2, TMPRSS2, IFITM3 and VDR polymorphisms with COVID-19 severity: A systematic review and meta-analysis , 2022, EXCLI journal.

[7]  Arthur S Slutsky,et al.  Renin-Angiotensin System Pathway Therapeutics Associated With Improved Outcomes in Males Hospitalized With COVID-19* , 2022, Critical care medicine.

[8]  L. Arendt,et al.  Breast cancer microenvironment and obesity: challenges for therapy , 2022, Cancer and Metastasis Reviews.

[9]  P. Kehoe,et al.  Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer’s Disease , 2022, The journals of gerontology. Series A, Biological sciences and medical sciences.

[10]  Jiraphun Jittikoon,et al.  Genetic polymorphisms of ACE1, ACE2, and TMPRSS2 associated with COVID‐19 severity: A systematic review with meta‐analysis , 2022, Reviews in medical virology.

[11]  P. Szymański,et al.  Risk factors for long-term survival in patients with ypN+ M0 rectal cancer after radical anterior resection , 2021, BMC Gastroenterology.

[12]  T. Gojobori,et al.  Angiotensin–Converting Enzyme (ACE) 1 Gene Polymorphism and Phenotypic Expression of COVID-19 Symptoms , 2021, Genes.

[13]  S. García-Ptacek,et al.  Brain Renin–Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer’s Disease , 2021, International journal of molecular sciences.

[14]  Xiaosheng Wang,et al.  Computational analysis of TMPRSS2 expression in normal and SARS-CoV-2-infected human tissues , 2021, Chemico-Biological Interactions.

[15]  F. Camacho,et al.  Associations between initiating antihypertensive regimens on stage I–III colorectal cancer outcomes: A Medicare SEER cohort analysis , 2021, Cancer medicine.

[16]  J. Manly,et al.  Blood-Brain Barrier Crossing Renin-Angiotensin Drugs and Cognition in the Elderly , 2021, Hypertension.

[17]  J. Sikora,et al.  Quadriceps muscle power and optimal shortening velocity are inversely related to angiotensin converting enzyme activity in older men , 2021, F1000Research.

[18]  C. Verschoor,et al.  MDSCs, ageing and inflammageing. , 2021, Cellular immunology.

[19]  A. Kurniawan,et al.  Anosmia/Hyposmia is a Good Predictor of Coronavirus Disease 2019 (COVID-19) Infection: A Meta-Analysis , 2020, International Archives of Otorhinolaryngology.

[20]  W. Seto,et al.  ACE (Angiotensin-Converting Enzyme) Inhibitors/Angiotensin Receptor Blockers Are Associated With Lower Colorectal Cancer Risk , 2020, Hypertension.

[21]  N. Lugito,et al.  Coronavirus disease 2019 and cardiovascular system: A narrative review , 2020, IJC Heart & Vasculature.

[22]  Koichi Yuki,et al.  COVID-19 pathophysiology: A review , 2020, Clinical Immunology.

[23]  J. Hoving,et al.  Coronavirus (COVID-19): , 2020, TBV – Tijdschrift voor Bedrijfs- en Verzekeringsgeneeskunde.

[24]  Jie Hao,et al.  Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection , 2020, Frontiers of Medicine.

[25]  R. Sengoku Aging and Alzheimer's disease pathology , 2019, Neuropathology : official journal of the Japanese Society of Neuropathology.

[26]  K. Williams,et al.  Hypertension in older adults: Assessment, management, and challenges , 2019, Clinical cardiology.

[27]  Z. Ruan,et al.  Angiotensin I-converting enzyme gene plays a crucial role in the pathology of carcinomas in colorectal cancer , 2019, Artificial cells, nanomedicine, and biotechnology.

[28]  J. Schmitt,et al.  Systematic review and meta-analysis of randomised controlled clinical trial evidence refutes relationship between pharmacotherapy with angiotensin-receptor blockers and an increased risk of cancer. , 2019, European journal of internal medicine.

[29]  V. Bueno,et al.  Immunosenescence: participation of T lymphocytes and myeloid-derived suppressor cells in aging-related immune response changes , 2019, Einstein.

[30]  A. Koyanagi,et al.  Angiotensin-Converting Enzyme Inhibitor Use and Incident Frailty: A Longitudinal Cohort Study , 2019, Drugs & Aging.

[31]  Jeffrey L. Cummings,et al.  Treatment Combinations for Alzheimer’s Disease: Current and Future Pharmacotherapy Options , 2019, Journal of Alzheimer's disease : JAD.

[32]  M. Khazaei,et al.  The Therapeutic Potential of Angiotensin-converting Enzyme and Angiotensin Receptor Inhibitors in the Treatment of Colorectal Cancer: Rational Strategies and Recent Progress. , 2019, Current pharmaceutical design.

[33]  L. Sakr,et al.  Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study , 2018, British Medical Journal.

[34]  M. Ishimura,et al.  Parameters of the Immune System and Vitamin D Levels in Old Individuals , 2018, Front. Immunol..

[35]  M. Carlson,et al.  Associations of Angiotensin Converting Enzyme-1 and Angiotensin II Blood Levels and Cognitive Function. , 2018, Journal of Alzheimer's disease : JAD.

[36]  M. Trivedi,et al.  Alterations in Gene Expression of Components of the Renin-Angiotensin System and Its Related Enzymes in Lung Cancer , 2017, Lung cancer international.

[37]  R. Stewart,et al.  Associations of centrally acting ACE inhibitors with cognitive decline and survival in Alzheimer’s disease , 2017, BJPsych Open.

[38]  Nikki M. Carroll,et al.  Effect of Angiotensin System Inhibitors on Survival in Patients Receiving Chemotherapy for Advanced Non–Small‐Cell Lung Cancer , 2017, Clinical lung cancer.

[39]  Lisa G. Pont,et al.  Challenges in the Management of Hypertension in Older Populations. , 2016, Advances in experimental medicine and biology.

[40]  P. Kehoe,et al.  Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology , 2016, Alzheimer's Research & Therapy.

[41]  B. Fabris,et al.  Update on RAAS Modulation for the Treatment of Diabetic Cardiovascular Disease , 2016, Journal of diabetes research.

[42]  R. Chappell,et al.  Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers , 2016, Cancer.

[43]  You-Ming Li,et al.  Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers therapy and colorectal cancer: a systematic review and meta-analysis , 2015, Cancer Causes & Control.

[44]  A. Aydıner,et al.  Renin-Angiotensin System Blockers May Prolong Survival of Metastatic Non-Small Cell Lung Cancer Patients Receiving Erlotinib , 2015, Medicine.

[45]  D. Cabrera,et al.  Renin‐Angiotensin System: An Old Player with Novel Functions in Skeletal Muscle , 2015, Medicinal research reviews.

[46]  J. Lord,et al.  Ageing and myeloid-derived suppressor cells: possible involvement in immunosenescence and age-related disease , 2014, AGE.

[47]  C. Cooper,et al.  ACE inhibitors, statins and thiazides: no association with change in grip strength among community dwelling older men and women from the Hertfordshire Cohort Study. , 2014, Age and ageing.

[48]  M. Mcmurdo,et al.  Do ACE Inhibitors Improve the Response to Exercise Training in Functionally Impaired Older Adults? A Randomized Controlled Trial , 2013, The journals of gerontology. Series A, Biological sciences and medical sciences.

[49]  W. M. van der Flier,et al.  The association of angiotensin-converting enzyme with biomarkers for Alzheimer’s disease , 2014, Alzheimer's Research & Therapy.

[50]  Jose M Garcia,et al.  Exposure to ACEI/ARB and β-Blockers Is Associated with Improved Survival and Decreased Tumor Progression and Hospitalizations in Patients with Advanced Colon Cancer. , 2013, Translational oncology.

[51]  M. Cesari,et al.  Angiotensin‐Converting Enzyme Inhibitors and Alzheimer's Disease Progression in Older Adults: Results from the Réseau sur la Maladie d'Alzheimer Français Cohort , 2013, Journal of the American Geriatrics Society.

[52]  K. Bernstein,et al.  Rediscovering ACE: novel insights into the many roles of the angiotensin-converting enzyme , 2013, Journal of Molecular Medicine.

[53]  K. Bernstein,et al.  A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme , 2013, Pharmacological Reviews.

[54]  S. Anton,et al.  Angiotensin‐Converting Enzyme Inhibitor Use by Older Adults Is Associated with Greater Functional Responses to Exercise , 2012, Journal of the American Geriatrics Society.

[55]  P. Kehoe,et al.  Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging , 2013, AGE.

[56]  A. Fu,et al.  Comorbid Conditions in Patients With Metastatic Colorectal Cancer , 2011, World journal of oncology.

[57]  E. Brandan,et al.  Fibrotic response induced by angiotensin-II requires NAD(P)H oxidase-induced reactive oxygen species (ROS) in skeletal muscle cells. , 2011, Biochemical and biophysical research communications.

[58]  C. Ward,et al.  Losartan Restores Skeletal Muscle Remodeling and Protects Against Disuse Atrophy in Sarcopenia , 2011, Science Translational Medicine.

[59]  Karl Swedberg,et al.  Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals , 2011, Journal of hypertension.

[60]  S. Studenski,et al.  Gait speed and survival in older adults. , 2011, JAMA.

[61]  S. Kjeldsen,et al.  Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. , 2011, The Lancet. Oncology.

[62]  R. Hannan,et al.  The renin–angiotensin system and cancer: old dog, new tricks , 2010, Nature Reviews Cancer.

[63]  D. Rowland,et al.  Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. , 2010, The Lancet. Oncology.

[64]  M. Cesari,et al.  Effects of ACE-inhibition on IGF-1 and IGFBP-3 concentrations in older adults with high cardiovascular risk profile , 2010, The journal of nutrition, health & aging.

[65]  J. Williamson,et al.  Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. , 2009, Archives of internal medicine.

[66]  Alnawaz Rehemtulla,et al.  AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist , 2009, Proceedings of the National Academy of Sciences.

[67]  A. Yoshihara,et al.  Physical Function Is Weakly Associated with Angiotensin-Converting Enzyme Gene I/D Polymorphism in Elderly Japanese Subjects , 2009, Gerontology.

[68]  R. Varadhan,et al.  The Use of Angiotensin‐converting Enzyme Inhibitors and Diuretics Is Associated With a Reduced Incidence of Impairment on Cognition in Elderly Women , 2008, Clinical pharmacology and therapeutics.

[69]  S. Love,et al.  Angiotensin‐converting enzyme (ACE) levels and activity in Alzheimer's disease, and relationship of perivascular ACE‐1 to cerebral amyloid angiopathy , 2008, Neuropathology and applied neurobiology.

[70]  D. Ribatti,et al.  Nonclassic Endogenous Novel Regulators of Angiogenesis , 2007, Pharmacological Reviews.

[71]  J. Silverman,et al.  Cardiovascular risk factors for Alzheimer's disease. , 2007, The American journal of geriatric cardiology.

[72]  S. Studenski,et al.  Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability. , 2006, JAMA.

[73]  S. Reis,et al.  The value of estimated functional capacity in estimating outcome: results from the NHBLI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study. , 2006, Journal of the American College of Cardiology.

[74]  S. Kritchevsky,et al.  Angiotensin-converting enzyme inhibition intervention in elderly persons: effects on body composition and physical performance. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[75]  D. Lloyd‐Jones,et al.  Hypertension in adults across the age spectrum: current outcomes and control in the community. , 2005, JAMA.

[76]  N. Rosenthal,et al.  Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. , 2005, The Journal of clinical investigation.

[77]  A. Roessner,et al.  The ectopeptidases CD10, CD13, CD26, and CD143 are upregulated in gastric cancer. , 2004, International journal of oncology.

[78]  O. Arrieta,et al.  Angiotensin II, cell proliferation and angiogenesis regulator: biologic and therapeutic implications in cancer. , 2004, Current vascular pharmacology.

[79]  Andrea Nuernberger,et al.  The effects of multidimensional home-based exercise on functional performance in elderly people. , 2004, The journals of gerontology. Series A, Biological sciences and medical sciences.

[80]  C. Bulpitt,et al.  Results of the pilot study for the Hypertension in the Very Elderly Trial , 2003, Journal of hypertension.

[81]  F. Luft,et al.  Angiotensin II and endothelin induce inflammation and thereby promote hypertension-induced end-organ damage. , 2003, Clinical nephrology.

[82]  J. Fornek,et al.  Captopril Prevents Experimental Autoimmune Myocarditis 1 , 2003, The Journal of Immunology.

[83]  T. Joh,et al.  Angiotensin-converting enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats. , 2003, Gastroenterology.

[84]  C. Fraga,et al.  Enalapril Attenuates Oxidative Stress in Diabetic Rats , 2001, Hypertension.

[85]  C. Hock,et al.  Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer’s dementia , 2001, Neurobiology of Aging.

[86]  B. Davis,et al.  Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP). , 2000, JAMA.

[87]  H. Krumholz,et al.  Pulse pressure and risk for myocardial infarction and heart failure in the elderly. , 2000, Journal of the American College of Cardiology.

[88]  M. Brown,et al.  Low-intensity exercise as a modifier of physical frailty in older adults. , 2000, Archives of physical medicine and rehabilitation.

[89]  S. Engeli,et al.  Physiology and pathophysiology of the adipose tissue renin-angiotensin system. , 2000, Hypertension.

[90]  C. Fraga,et al.  Enalapril and captopril enhance glutathione-dependent antioxidant defenses in mouse tissues. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[91]  M. Shoji,et al.  Angiotensin-converting enzyme genotype is associated with Alzheimer disease in the Japanese population , 1999, Neuroscience Letters.

[92]  C. Fraga,et al.  Higher levels of antioxidant defenses in enalapril-treated versus non-enalapril-treated hemodialysis patients. , 1999, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[93]  H. Lithell,et al.  Skeletal muscle angiotensin-converting enzyme and its relationship to blood pressure in primary hypertension and healthy elderly men. , 1999, Blood pressure.

[94]  M. Owen,et al.  Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease , 1999, Nature Genetics.

[95]  K. Swedberg,et al.  Angiotensin-converting enzyme gene expression in skeletal muscle in patients with chronic heart failure. , 1998, Journal of cardiac failure.

[96]  E. Ventura,et al.  Captopril and lisinopril suppress production of interleukin-12 by human peripheral blood mononuclear cells. , 1998, Immunology letters.

[97]  H. Lithell,et al.  Angiotensin-converting enzyme in human skeletal muscle. A simple in vitro assay of activity in needle biopsy specimens. , 1994, Scandinavian journal of clinical and laboratory investigation.

[98]  E. U. Makov,et al.  Effect of converting enzyme inhibitor captopril on T cell functions in essential hypertension. , 1991, Nephron.

[99]  N. Hooper,et al.  Angiotensin converting enzyme: implications from molecular biology for its physiological functions. , 1991, The International journal of biochemistry.

[100]  E. Perry,et al.  Angiotensin Converting Enzyme in Alzheimer's Disease: Increased Activity in Caudate Nucleus and Cortical Areas , 1982, Journal of neurochemistry.