The Klotho protein supports redox balance and metabolic functions of cardiomyocytes during ischemia/reperfusion injury

Olejnik, Agnieszka; Banaszkiewicz, Marta; Krzywonos‐Zawadzka, Anna; Bil‐Lula, Iwona

doi:10.5603/cj.a2021.0174

Cited by 6 publications

(9 citation statements)

References 52 publications

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“…In our previous research, we showed that Klotho improved the viability and metabolic activity of the cardiomyocytes during IRI, and was proposed as a biomarker of heart damage [ 16 ]. We then showed a supported redox balance by means of Klotho protein in injured cardiac cells [ 17 ]. For this reason, we hypothesized that through the reduction of oxidative stress, Klotho may break the cascade involved in IRI.…”

Section: Discussionmentioning

confidence: 99%

“…Our further studies showed that the administration of the nitric oxide synthase, MMP-2 and myosin light chain kinase inhibitors led to cardioprotection in the human cardiomyocytes or the isolated rat hearts [ 7 , 35 , 36 ]. We then proved that Klotho protein participates in the regulation of a redox balance and supports metabolic homeostasis of the cardiomyocytes [ 17 ]. In the current research, increased injury in the cells subjected to IRI was shown.…”

Section: Discussionmentioning

confidence: 99%

“…Supplementation with Klotho led to an increased viability and metabolic activity of injured cells [ 16 ]. Importantly, we recently showed that Klotho protein participates in the regulation of the redox balance and supports metabolic homeostasis of the cardiomyocytes [ 17 ]. Therefore, Klotho protein may protect the cardiac cells by the inhibition of oxidative stress and subsequent degradation of contractile proteins.…”

Section: Introductionmentioning

confidence: 99%

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Klotho Protein Decreases MMP-Mediated Degradation of Contractile Proteins during Ischaemia/Reperfusion Injury to the Cardiomyocytes

Olejnik

Krzywonos‐Zawadzka

Banaszkiewicz

et al. 2022

IJMS

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Ischaemia, followed by reperfusion, causes the generation of reactive oxygen species, overproduction of peroxynitrite, activation of matrix metalloproteinases (MMPs), and subsequently the degradation of heart contractile proteins in the cardiomyocytes. Klotho is a membrane-bound or soluble protein that regulates mineral metabolism and has antioxidative activity. This study aimed to examine the influence of Klotho protein on the MMP-mediated degradation of contractile proteins during ischaemia/reperfusion injury (IRI) to the cardiomyocytes. Human cardiac myocytes (HCM) underwent in vitro chemical IRI (with sodium cyanide and deoxyglucose), with or without the administration of recombinant Klotho protein. The expression of MMP genes, the expression and activity of MMP proteins, as well as the level of contractile proteins such as myosin light chain 1 (MLC1) and troponin I (TnI) in HCM were measured. Administration of Klotho protein resulted in a decreased activity of MMP-2 and reduced the release of MLC1 and TnI that followed in cells subjected to IRI. Thus, Klotho protein contributes to the inhibition of MMP-dependent degradation of contractile proteins and prevents injury to the cardiomyocytes during IRI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Klotho Protein Decreases MMP-Mediated Degradation of Contractile Proteins during Ischaemia/Reperfusion Injury to the Cardiomyocytes

Olejnik

Krzywonos‐Zawadzka

Banaszkiewicz

et al. 2022

IJMS

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“…Neuregulin-1 attenuates oxidative stress and inflammation by inhibiting Nox4 and NLR family pyrin domain containing 3 (NLRP3)/caspase-1 in myocardial I/R injury [ 56 ]. Klotho, an anti-aging single-pass membrane protein, decreases Nox2 and Nox4 levels in cardiomyocytes during I/R [ 57 ]. These upstream regulators of Nox2 and Nox4 are potential targets for the treatment of myocardial I/R injury.…”

Section: Novel Regulatory Mechanisms Of Nox and Its Crosstalk With Ot...mentioning

confidence: 99%

Yin and Yang of NADPH Oxidases in Myocardial Ischemia-Reperfusion

Matsushima

Sadoshima

2022

Antioxidants

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Oxidative stress is critically involved in the pathophysiology of myocardial ischemic-reperfusion (I/R) injury. NADPH oxidase (Nox) 2 and 4, major sources of reactive oxygen species (ROS) in cardiomyocytes, are upregulated in response to I/R. Suppression of Nox-derived ROS prevents mitochondrial dysfunction and endoplasmic reticulum (ER) stress, leading to attenuation of myocardial I/R injury. However, minimal levels of ROS by either Nox2 or Nox4 are required for energy metabolism during I/R in the heart, preserving hypoxia-inducible factor-1α (HIF-1α) and peroxisome proliferator-activated receptor-α (PPARα) levels. Furthermore, extreme suppression of Nox activity induces reductive stress, leading to paradoxical increases in ROS levels. Nox4 has distinct roles in organelles such as mitochondria, ER, and ER-mitochondria contact sites (MAMs). Mitochondrial Nox4 exerts a detrimental effect, causing ROS-induced mitochondrial dysfunction during I/R, whereas Nox4 in the ER and MAMs is potentially protective against I/R injury through regulation of autophagy and MAM function, respectively. Although Nox isoforms are potential therapeutic targets for I/R injury, to maximize the effect of intervention, it is likely important to optimize the ROS level and selectively inhibit Nox4 in mitochondria. Here, we discuss the ‘Yin and Yang’ functions of Nox isoforms during myocardial I/R.

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“…Кардиомиоциты человека подверглись химическому И/Р-повреждению in vitro (с цианистым натрием и 2-дезоксиглюкозой) в присутствии или в отсутствие Re-KL. Введение белка Klotho привело к уменьшению повреждения, снижению уровня NOX2 и NOX4, уменьшению образования АФК, активных форм азота и H 2 O 2 , снижению экспрессии индуцируемой NOS и ограничению продукции нитратов/нитритов в клетках при ишемии/реперфузии [68].…”

Section: роль белка Klotho при атеросклерозе и связанных с ним заболе...unclassified

Klotho protein and atherosclerotic cardiovascular diseases: prolonging the thread of life

Alieva

Reznik

Teplova

et al. 2022

Medical Journal of the Russian Federation

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To date, the most widely used biomarkers are natriuretic peptides and cardiac troponins. Many other biomarkers have also been identified, but only a few of them have found application in actual clinical practice. This review focuses on the Klotho protein and its role in cardiovascular diseases. In 1997, a gene that slows down the aging process was identified. It was named Klotho (Greek, ώ, spinning; Latin, Clotho; English, Klotho) in honor of the goddess of ancient Greek mythology, spinning the thread of life and being the personification of the steady, calm course of fate. Mice with an insertional mutation in the region of the Klotho gene promoter were characterized by premature aging processes. Three families of Klotho are known: -Klotho, -Klotho, and -Klotho, and the most studied is -Klotho. The Klotho protein consists of a large extracellular domain and a short C-terminal intracellular region. The extracellular domain consists of two repeat sequences called KL1 and KL2. -Klotho and -Klotho contain the KL1 and KL2 domains, respectively, and -Klotho contains only the KL1 domain. The Klotho gene in humans is located on chromosome 13q12 and consists of five exons. The Klotho protein is mainly expressed in the distal convoluted tubules of the kidneys and the vascular epithelial plexus of the cerebral ventricles. At lower concentrations, the Klotho gene is also found in other organs and tissues, particularly in the heart. Many studies have demonstrated the protective role of the Klotho protein in cardiovascular pathology. The pleiotropic properties of this protein are reflected in the diversity and interaction of cardioprotective mechanisms. The regulation of the concentrations of the Klotho protein in the blood and its expression in heart cells with the help of drugs can play a significant role in cellular metabolism and represent a promising target for the treatment of heart and vascular pathologies.

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The Klotho protein supports redox balance and metabolic functions of cardiomyocytes during ischemia/reperfusion injury

Abstract: This article has been peer reviewed and published immediately upon acceptance.It is an open access article, which means that it can be downloaded, printed, and distributed freely, provided the work is properly cited. Articles in "Cardiology Journal" are listed in PubMed.

Cited by 6 publications

References 52 publications

Klotho Protein Decreases MMP-Mediated Degradation of Contractile Proteins during Ischaemia/Reperfusion Injury to the Cardiomyocytes

Klotho Protein Decreases MMP-Mediated Degradation of Contractile Proteins during Ischaemia/Reperfusion Injury to the Cardiomyocytes

Yin and Yang of NADPH Oxidases in Myocardial Ischemia-Reperfusion

Klotho protein and atherosclerotic cardiovascular diseases: prolonging the thread of life

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