Increased Kinin Levels and Decreased Responsiveness to Kinins During Aging

Pérez, Viviana; Velarde, Victoria; Acuña-Castillo, Claudio; Gómez, Christian R.; Nishimura, Sumiyo; Sabaj, Valeria; Walter, Robin; Sierra, Felipe

doi:10.1093/gerona/60.8.984

Cited by 13 publications

(11 citation statements)

References 30 publications

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confidence: 99%

“…Moreover, aging is associated with a decreased availability of cardiac BK B2 receptors 16 and in some occasions with a blunted endothelium-dependent vasodilator response to BK. 17,18 In addition, combined B2 receptor knockout and diabetes mellitus in mice lead to an accelerated aging phenotype that is coupled to an increase of oxidative stress and an increase in ACE enzyme levels. 19 Therefore, the protective effect of BK might also relate to the prevention of cellular senescence, in particular, of the endothelium.…”

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confidence: 99%

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Bradykinin Protects Against Oxidative Stress–Induced Endothelial Cell Senescence

Oeseburg¹,

Iusuf²,

Harst³

et al. 2009

Hypertension

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Abstract-Premature aging (senescence) of endothelial cells might play an important role in the development and progression of hypertension and atherosclerosis. We hypothesized that bradykinin, a hormone that mediates vasoprotective effects of angiotensin-converting enzyme inhibitors, protects endothelial cells from oxidative stressinduced senescence. Bradykinin treatment (0.001 to 1 nmol/L) dose-dependently decreased senescence induced by 25 mol/L of H 2 O 2 in cultured bovine aortic endothelial cells, as witnessed by a complete inhibition of increased senescent cell numbers and a 34% reduction of the levels of the senescence-associated cell cycle protein p21. Because H 2 O 2 induces senescence through superoxide-induced DNA damage, single-cell DNA damage was measured by comet assay. Bradykinin reduced DNA damage to control levels. The protective effect of bradykinin also resulted in a significant increase in the migration of H 2 O 2 -treated bovine aorta endothelial cells in an in vitro endothelial injury model, or "scratch" assay. The protective effect of bradykinin was abolished by the bradykinin B2 receptor antagonist HOE-140 and the NO production inhibitor N -methyl-L-arginine acetate salt. Therefore, we conclude that bradykinin protects endothelial cells from superoxide-induced senescence through bradykinin B2 receptor-and NO-mediated inhibition of DNA damage. Key Words: senescence Ⅲ endothelial Ⅲ bradykinin Ⅲ reactive oxygen species Ⅲ DNA damage A ging-related vascular dysfunction is believed to be an important contributor to vascular pathogenesis and a worsened prognosis. 1,2 Hypertension, one of the main risk factors for a number of cardiovascular diseases, is characterized by an accelerated development of age-related endothelial dilator dysfunction. 3 Therefore, the development of therapeutic strategies directed against age-related endothelial function decline will be an important step toward the prevention and treatment of age-related vascular diseases, such as hypertension and coronary artery disease.Endothelial cell senescence is a cyclin-dependent kinase inhibitor 1A (p21) proliferative arrest 4 that can be induced by DNA damage caused by exposure to reactive oxygen species (ROS). 5 There are several reasons to assume that endothelial cell senescence is involved in vascular pathogenesis. Senescent endothelial cells show deleterious functional changes (eg, decreased release of endothelial-derived relaxing factors, increased release of endothelial-derived constricting factors, and increased production of molecules that are associated with inflammation). 6,7 These features are reminiscent of the aberrant endothelial changes observed in aging and atherosclerosis. 8 Moreover, an increase of senescent endothelial cells and senescence markers is observed in the vasculature of atherosclerotic patients and in aged rodents with endothelial dysfunction. 8,9 Angiotensin-converting enzyme (ACE) inhibitors effectively protect against the progression of chronic atherosclerotic disease, endothelial dysfunction, an...

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confidence: 99%

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confidence: 99%

Bradykinin Protects Against Oxidative Stress–Induced Endothelial Cell Senescence

Oeseburg¹,

Iusuf²,

Harst³

et al. 2009

Hypertension

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“…C1-INH-HAE results from the uncontrolled release of bradykinin from high molecular weight kininogen (HMWK) due to the de ciency of functional C1-INH. Previous studies have observed the level of kininogen increased with age in rat serum [17][18][19][20] . However, aging leads to weaker responsiveness to kinins [8] which is believed to be realized by the decreased density of the bradykinin receptors, lessening the vasoactive effects of bradykinin on the heart and vasculature [21][22][23] .…”

Section: Discussionmentioning

confidence: 84%

The Natural Course of Hereditary Angioedema in a Chinese Cohort

Cao

Liu

Zhi³

2020

Preprint

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Background: Hereditary angioedema (HAE) is a rare disease with potential life-threatening risks. To study the natural course of HAE under therapy-free conditions throughout patient life is essential for practitioners and patients to avoid possible risk factors and guide treatment.Objectives: Describe the natural course of HAE and explore possible risk factors, providing new clues for guiding clinical prevention and treatment.Methods: A web-based survey was conducted in 103 Chinese patients with type 1 HAE. Disease progression at different age stages was provided by each participant. The data for exploring the natural course of HAE composed of two parts: one came from the participants who had never adopted any prophylactic drug for HAE; the other was from the patients with a history of medication, but only the periods before they got confirmed diagnosis and received medications were analyzed. The demographic characteristics, lifestyles, disease severity, and family history were also collected.Results: Among 103 patients, 14 (13.6%) had their first HAE attack before ten years old and 51 (49.5%) between 10 and 19. The disease worsened in 83.3% of the patients in their twenties. The proportion of patients with symptoms alleviated increased after the age of 30 years old, but the disease maintained relatively severe in most cases before 50. The participants also reported 233 members shared similar symptoms of angioedema in their family and 30 had died of laryngeal edema with the median death age of 46 years old. The disease severity was not observed to be affected significantly by gender, BMI, alcohol or smoking.Conclusions: We summarized HAE progression patterns under therapy-free conditions, showing the natural course of HAE development along with aging. Long-term prophylaxis and symptomatic treatment are recommended for all HAE patients, especially young and middle-aged and might be adjusted depending on the disease progression.

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“…Aging does not only affect the KKK system through the ACE/ACE2 balance, but also directly altering the pharmacology of BR1 and BR2. It has been observed that although the serum levels of kinins increase with age, the responsiveness of target cells is limited or altered [ 106 ]. In this respect, bradykinin-induced vasorelaxation is actually affected by the BR1/BR2 ratio in the vasculature [ 107 ].…”

Section: Pathophysiological Contributions Of Covid-19 Risk Factorsmentioning

confidence: 99%

Identifying pathophysiological bases of disease in COVID-19

et al. 2020

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COVID-19 is an infectious disease caused by the SARS-CoV-2 virus that can affect lung physiology encompassing a wide spectrum of severities, ranging from asymptomatic and mild symptoms to severe and fatal cases; the latter including massive neutrophil infiltration, stroke and multiple organ failure. Despite many recents findings, a clear mechanistic description underlying symptomatology is lacking. In this article, we thoroughly review the available data involving risk factors, age, gender, comorbidities, symptoms of disease, cellular and molecular mechanisms and the details behind host/pathogen interaction that hints at the existence of different pathophysiological mechanisms of disease. There is clear evidence that, by targeting the angiotensin-converting enzyme II (ACE2) –its natural receptor–, SARS-CoV-2 would mainly affect the renin-angiotensin-aldosterone system (RAAS), whose imbalance triggers diverse symptomatology-associated pathological processes. Downstream actors of the RAAS cascade are identified, and their interaction with risk factors and comorbidities are presented, rationalizing why a specific subgroup of individuals that present already lower ACE2 levels is particularly more susceptible to severe forms of disease. Finally, the notion of endotype discovery in the context of COVID-19 is introduced. We hypothesize that COVID-19, and its associated spectrum of severities, is an umbrella term covering different pathophysiological mechanisms (endotypes). This approach should dramatically accelerate our understanding and treatment of disease(s), enabling further discovery of pathophysiological mechanisms and leading to the identification of specific groups of patients that may benefit from personalized treatments.

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Increased Kinin Levels and Decreased Responsiveness to Kinins During Aging

Cited by 13 publications

References 30 publications

Bradykinin Protects Against Oxidative Stress–Induced Endothelial Cell Senescence

Bradykinin Protects Against Oxidative Stress–Induced Endothelial Cell Senescence

The Natural Course of Hereditary Angioedema in a Chinese Cohort

Identifying pathophysiological bases of disease in COVID-19

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