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The Role of Inducible Nitric Oxide Synthase (iNOS) in Human Myocardial Infarction

Wilmes, Verena (2023)
The Role of Inducible Nitric Oxide Synthase (iNOS) in Human Myocardial Infarction.
Technische Universität Darmstadt
doi: 10.26083/tuprints-00026333
Dissertation, Erstveröffentlichung, Verlagsversion

Kurzbeschreibung (Abstract)

Cardiovascular diseases (CVDs), which include disorders of the heart and its blood vessels, such as myocardial infarction (MI), are the leading cause of death globally. During MI necrosis of myocardial cells leads to inflammation and fibrosis. Cardiac scarring and subsequently adverse remodeling, negatively impact myocardial healing and may lead to further disease states after MI, such as hypertension, heart failure, and death. While elevated levels of cardiac-specific troponins (cTnT and cTnI), as well as cardiac specific creatine kinase (CK-MB) are central biomarkers for the diagnosis of MI, interleukins, natriuretic peptides, matrix metallopeptidases (MMPs) and noncoding RNAs are currently discussed as biomarkers for adverse cardiac remodeling after MI. Nevertheless, a thorough understanding of the molecular processes during MI may lead to further biomarkers or improved therapy options. Inducible nitric oxide synthase (iNOS) is one of the three NOS isoforms that produce nitric oxide (NO). It is induced by stimuli such as inflammation and hypoxia and has been described in patients with end-stage heart failure, cardiomyopathy and ischemic heart disease. In murine and rabbit models of MI increased iNOS expression is suggested to contribute to left ventricular dysfunction, heart failure progression, myocardial injury and extent of infarct size, even late after ischemia and reperfusion. These detrimental effects are due to the reaction of iNOS derived NO with superoxide anion (O2-), which leads to reactive intermediates that can nitrate, nitrosate or oxidize their biological environment. This oxidative nitrosative stress promotes DNA damage, suppresion of DNA-repair enzymes and post-translational modifications of proteins. Specifically, peroxynitrite (ONOO-) is formed by the reaction of NO with O2- and is a strong oxidant causing nitrosylation of proteins and the formation of nitrotyrosine. Further peroxynitrite inactivates anti-proteases and activates MMPs, that are known for degrading and remodeling extracellular matrix under physiological and pathological conditions, leading to left ventricular remodeling after MI. Hence, understanding the role of iNOS in MI may lead to improved therapy options and to the development of biomarkers for the progression of heart failure after MI. In the present thesis the role of iNOS in human MI is thoroughly examined for the first time. It includes genetic and cellular approaches to determine the iNOS expression and factors influencing iNOS expression in human MI tissue. Further, methods of measuring iNOS derived oxidative stress are established. Especially, the present work emphasizes the differences in iNOS expression between animal models of MI and human MI. The first study focused on examining iNOS mRNA and protein levels in postmortem human MI hearts. A significant increase of iNOS mRNA in infarcted and non-infarcted tissue was detected, in comparison to healthy controls. Further, significantly increased iNOS protein levels were found in infarcted and non-infarcted regions. Interestingly, iNOS was predominantly found in “M2” resident macrophages and to a smaller amount in “M1” inflammatory macrophages. Accordingly, the significant increase in iNOS protein in infarcted regions was seen in the “M2” resident macrophages. In cardiomyocytes no iNOS protein expression was detected. A distance analysis between iNOS+ and nitrotyrosine (NT)+ cells revealed that NT+ cells peak within 10-15 µm of iNOS, suggesting a dependence and a range of activity by iNOS produced NO. The second study examined microRNAs as posttranscriptional regulators of the iNOS expression. The expression of miR-939, miR-21 and miR-30e was measured and correlated with iNOS mRNA and protein levels in postmortem human MI hearts. miR-939 is known to decrease cytokine induced iNOS protein expression and NO synthesis in human hepatocytes. miR-21 has its strongest expression in cardiac macrophages in mice, where it is the strongest expressed miRNA among all cardiac miRNAs. The function of miR-21 in fibroblasts comprises of regulating fibroblast proliferation and fibrosis. miR-30e is described as downregulated in hypoxic cardiomyocytes and MI tissue of rats to protect the myocardium via enhancing cardiomyocyte viability and inhibiting apoptosis. The results revealed significant upregulation of miR-939, miR-21 and miR-30e in infarcted and non-infarcted regions of postmortem human MI hearts in comparison to healthy controls. Correlation analysis showed a significant correlation between miR-939 expression and the iNOS mRNA expression in the control group and the infarcted regions, which was more pronounced in the controls. A massive iNOS activation might exceed the capability of miR-939 to keep its expression in balance. On the other hand, miR-30e and miR-21 did not seem to influence cardiac iNOS levels in MI or macrophage polarization. In the third study, the iNOS gene NOS2 was genotyped for the (CCTTT)n repeat polymorphism in the promoter region, the rs2779249, G>T single nucleotid polymorphism (SNP) -1026 basepairs (bp) before transcription start and the rs2297518, C>T SNP at exon 16. These polymorphisms are known to influence the iNOS expression and subsequently oxidative stress in atrial fibrilliation and hypertension amongst others. In the MI group we found an accumulation of NOS2 risk polymorphisms, such as long (CCTTT)n repeat polymorphisms or the T alleles at rs2779249, G>T and rs2297518, C>T in contrast to healthy controls. Additionally, we detected an increase in iNOS protein levels, in the control and MI group, when NOS2 risk polymorphisms were present. Serum levels of malondialdehyde (MDA), a marker of oxidative stress, of creatinine, an independent risk factor for and after MI and of nitrate/nitrite (NOx), which are known the reflect the activity of iNOS, were increased in the MI group in comparison to the controls. Further, in the MI group homozygous carriers of the long (CCTTT)n repeat had increased serum MDA levels in comparison to heterozygote carriers or carriers of short (CCTTT)n repeats. Homozygous carriers of the T allele at rs2779249, G>T in the MI group showed increased serum levels of nitrate and creatinine. This suggests a connection between serum markers and NOS2 risk polymorphism in MI, however, no direct influence of risk polymorphisms on cardiac iNOS levels was observed. In conclusion the present thesis revealed increased iNOS mRNA expression in postmortem human infarction hearts and increased iNOS protein production. Interestingly, iNOS is predominantly expressed in “M2”-resident macrophages and upon MI, the iNOS production is even more increased in these macrophages. Since NT+ cells peak within 10-15µm of iNOS+ cells, this could represent an activity range of iNOS and subsequent oxidative stress production within that perimeter. miR-939 seems to regulate the iNOS expression posttranscriptional, however, upon MI this regulation is not efficiently to keep the iNOS mRNA level at bay. Risk polymorphisms in the NOS2 gene accumulate in the MI group and seem to enhance iNOS protein expression. This may lead to increased oxidative stress and adverse cardiac remodeling after MI. The seen increased serum levels of MDA, creatinine and NOx in the MI group could not be correlated with cardiac iNOS mRNA and protein levels. However, long (CCTTT)n repeats and the homozygous T-allele at rs2779249, G>T seem to influence serum MDA, creatinine and nitrate level in the MI group. The role of iNOS in MI seems complex, however we could reveal increased oxidative stress upon MI, by increased iNOS production. Hence, increased iNOS expression and activity due to certain risk polymorphisms may impair the healing process after MI, lead to adverse remodeling and further heart diseases such as heart failure.

Typ des Eintrags: Dissertation
Erschienen: 2023
Autor(en): Wilmes, Verena
Art des Eintrags: Erstveröffentlichung
Titel: The Role of Inducible Nitric Oxide Synthase (iNOS) in Human Myocardial Infarction
Sprache: Englisch
Referenten: Thiel, Prof. Dr. Gerhard ; Kauferstein, Prof. Dr. Silke ; Galuske, Prof. Dr. Ralf ; Nuber, Prof. Dr. Ulrike
Publikationsjahr: 21 November 2023
Ort: Darmstadt
Kollation: 67 Seiten
Datum der mündlichen Prüfung: 5 Oktober 2023
DOI: 10.26083/tuprints-00026333
URL / URN: https://tuprints.ulb.tu-darmstadt.de/26333
Kurzbeschreibung (Abstract):

Cardiovascular diseases (CVDs), which include disorders of the heart and its blood vessels, such as myocardial infarction (MI), are the leading cause of death globally. During MI necrosis of myocardial cells leads to inflammation and fibrosis. Cardiac scarring and subsequently adverse remodeling, negatively impact myocardial healing and may lead to further disease states after MI, such as hypertension, heart failure, and death. While elevated levels of cardiac-specific troponins (cTnT and cTnI), as well as cardiac specific creatine kinase (CK-MB) are central biomarkers for the diagnosis of MI, interleukins, natriuretic peptides, matrix metallopeptidases (MMPs) and noncoding RNAs are currently discussed as biomarkers for adverse cardiac remodeling after MI. Nevertheless, a thorough understanding of the molecular processes during MI may lead to further biomarkers or improved therapy options. Inducible nitric oxide synthase (iNOS) is one of the three NOS isoforms that produce nitric oxide (NO). It is induced by stimuli such as inflammation and hypoxia and has been described in patients with end-stage heart failure, cardiomyopathy and ischemic heart disease. In murine and rabbit models of MI increased iNOS expression is suggested to contribute to left ventricular dysfunction, heart failure progression, myocardial injury and extent of infarct size, even late after ischemia and reperfusion. These detrimental effects are due to the reaction of iNOS derived NO with superoxide anion (O2-), which leads to reactive intermediates that can nitrate, nitrosate or oxidize their biological environment. This oxidative nitrosative stress promotes DNA damage, suppresion of DNA-repair enzymes and post-translational modifications of proteins. Specifically, peroxynitrite (ONOO-) is formed by the reaction of NO with O2- and is a strong oxidant causing nitrosylation of proteins and the formation of nitrotyrosine. Further peroxynitrite inactivates anti-proteases and activates MMPs, that are known for degrading and remodeling extracellular matrix under physiological and pathological conditions, leading to left ventricular remodeling after MI. Hence, understanding the role of iNOS in MI may lead to improved therapy options and to the development of biomarkers for the progression of heart failure after MI. In the present thesis the role of iNOS in human MI is thoroughly examined for the first time. It includes genetic and cellular approaches to determine the iNOS expression and factors influencing iNOS expression in human MI tissue. Further, methods of measuring iNOS derived oxidative stress are established. Especially, the present work emphasizes the differences in iNOS expression between animal models of MI and human MI. The first study focused on examining iNOS mRNA and protein levels in postmortem human MI hearts. A significant increase of iNOS mRNA in infarcted and non-infarcted tissue was detected, in comparison to healthy controls. Further, significantly increased iNOS protein levels were found in infarcted and non-infarcted regions. Interestingly, iNOS was predominantly found in “M2” resident macrophages and to a smaller amount in “M1” inflammatory macrophages. Accordingly, the significant increase in iNOS protein in infarcted regions was seen in the “M2” resident macrophages. In cardiomyocytes no iNOS protein expression was detected. A distance analysis between iNOS+ and nitrotyrosine (NT)+ cells revealed that NT+ cells peak within 10-15 µm of iNOS, suggesting a dependence and a range of activity by iNOS produced NO. The second study examined microRNAs as posttranscriptional regulators of the iNOS expression. The expression of miR-939, miR-21 and miR-30e was measured and correlated with iNOS mRNA and protein levels in postmortem human MI hearts. miR-939 is known to decrease cytokine induced iNOS protein expression and NO synthesis in human hepatocytes. miR-21 has its strongest expression in cardiac macrophages in mice, where it is the strongest expressed miRNA among all cardiac miRNAs. The function of miR-21 in fibroblasts comprises of regulating fibroblast proliferation and fibrosis. miR-30e is described as downregulated in hypoxic cardiomyocytes and MI tissue of rats to protect the myocardium via enhancing cardiomyocyte viability and inhibiting apoptosis. The results revealed significant upregulation of miR-939, miR-21 and miR-30e in infarcted and non-infarcted regions of postmortem human MI hearts in comparison to healthy controls. Correlation analysis showed a significant correlation between miR-939 expression and the iNOS mRNA expression in the control group and the infarcted regions, which was more pronounced in the controls. A massive iNOS activation might exceed the capability of miR-939 to keep its expression in balance. On the other hand, miR-30e and miR-21 did not seem to influence cardiac iNOS levels in MI or macrophage polarization. In the third study, the iNOS gene NOS2 was genotyped for the (CCTTT)n repeat polymorphism in the promoter region, the rs2779249, G>T single nucleotid polymorphism (SNP) -1026 basepairs (bp) before transcription start and the rs2297518, C>T SNP at exon 16. These polymorphisms are known to influence the iNOS expression and subsequently oxidative stress in atrial fibrilliation and hypertension amongst others. In the MI group we found an accumulation of NOS2 risk polymorphisms, such as long (CCTTT)n repeat polymorphisms or the T alleles at rs2779249, G>T and rs2297518, C>T in contrast to healthy controls. Additionally, we detected an increase in iNOS protein levels, in the control and MI group, when NOS2 risk polymorphisms were present. Serum levels of malondialdehyde (MDA), a marker of oxidative stress, of creatinine, an independent risk factor for and after MI and of nitrate/nitrite (NOx), which are known the reflect the activity of iNOS, were increased in the MI group in comparison to the controls. Further, in the MI group homozygous carriers of the long (CCTTT)n repeat had increased serum MDA levels in comparison to heterozygote carriers or carriers of short (CCTTT)n repeats. Homozygous carriers of the T allele at rs2779249, G>T in the MI group showed increased serum levels of nitrate and creatinine. This suggests a connection between serum markers and NOS2 risk polymorphism in MI, however, no direct influence of risk polymorphisms on cardiac iNOS levels was observed. In conclusion the present thesis revealed increased iNOS mRNA expression in postmortem human infarction hearts and increased iNOS protein production. Interestingly, iNOS is predominantly expressed in “M2”-resident macrophages and upon MI, the iNOS production is even more increased in these macrophages. Since NT+ cells peak within 10-15µm of iNOS+ cells, this could represent an activity range of iNOS and subsequent oxidative stress production within that perimeter. miR-939 seems to regulate the iNOS expression posttranscriptional, however, upon MI this regulation is not efficiently to keep the iNOS mRNA level at bay. Risk polymorphisms in the NOS2 gene accumulate in the MI group and seem to enhance iNOS protein expression. This may lead to increased oxidative stress and adverse cardiac remodeling after MI. The seen increased serum levels of MDA, creatinine and NOx in the MI group could not be correlated with cardiac iNOS mRNA and protein levels. However, long (CCTTT)n repeats and the homozygous T-allele at rs2779249, G>T seem to influence serum MDA, creatinine and nitrate level in the MI group. The role of iNOS in MI seems complex, however we could reveal increased oxidative stress upon MI, by increased iNOS production. Hence, increased iNOS expression and activity due to certain risk polymorphisms may impair the healing process after MI, lead to adverse remodeling and further heart diseases such as heart failure.

Alternatives oder übersetztes Abstract:
Alternatives AbstractSprache

Kardiovaskuläre Erkrankungen, zu denen der Myokardinfarkt gehört, sind weltweit die führende Todesursache. Beim Myokardinfarkt kommt es zur Nekrose von Kardiomyozyten, was zu Entzündungen und Fibrose führt. Die Folgen sind ein Umbau des Gewebes und Narbengewebe, welche den Heilungsprozess beeinträchtigen und zu weiteren Erkrankungen wie Herzrhythmusstörungen und Herzinsuffizienz führen können. Erhöhte Blutkonzentrationen von myokardialem Troponin (cTnT und cTnI) und der Creatinkinase (CK-MB) sind zentrale Biomarker bei der Diagnostizierung eines Herzinfarktes. Zur Erkennung des kardialen Remodeling und der möglichen Folgeerkrankungen werden Interleukine, natiuretische Peptide, Matrixmetallopeptidasen und nichtkodierende RNAs erforscht. Ein verbessertes Verständnis der molekularen Prozesse bei Myokardinfarkt kann zur Entdeckung weiterer Biomarker oder zu weiteren Therapieoptionen nach Myokardinfarkt beitragen. Die induzierbare Stickoxidsynthase (iNOS) ist eine der drei NOS Isoformen, die Stickstoffmonoxid (NO) produzieren. iNOS wird durch Entzündungen oder Hypoxie induziert und die iNOS Expression wurde in Patienten mit diversen kardiovaskulären Erkrankungen nachgewiesen. Zur iNOS Expression im Myokardinfarkt gibt es bislang nur Tierstudien, die einen Beitrag der iNOS zur linksventrikulären Dysfunktion, fortschreitender Herzinsuffizienz, myokardialen Verletzungen und größeren Infarktnarben beschreiben. Diese schädlichen Effekte der iNOS werden der Reaktion von NO mit dem Superoxidanion (O2-) zugeschrieben, was die Entstehung von Peroxynitrit (ONOO-) zur Folge hat. Peroxynitrit hat wie alle Sauerstoffradiale eine Nitrierung oder Oxidierung der biologischen Umgebung zur Folge. Oxidativer bzw. nitrosativer Stress dieser Art schädigt die DNA, DNA-Reparaturenzyme und führt zu posttranslationalen Proteinmodifizierungen. Insbesondere Peroxynitrit führt zur Nitrosylierung von Tyrosinresten der Proteine, wodurch Nitrotyrosin entsteht. Des Weiteren aktiviert Peroxynitrit die Matrixmetallopeptidasen, was einen Ab- und Umbau der extrazellulären Matrix zur Folge hat, wodurch linksventrikuläres Remodeling entstehen kann. Dementsprechend stellt ein verbessertes Verständnis der Rolle der iNOS bei Myokardinfarkt einen wichtigen Baustein dar, für verbesserte Therapieoptionen, aber auch für die Entwicklung von Biomarkern für fortschreitende Herzinsuffizenz nach Myokardinfarkt. In der vorliegenden Doktorarbeit wurde zum ersten Mal die Rolle der iNOS im humanen Myokardinfarkt untersucht. Es wurden sowohl genetische, als auch zelluläre Methoden angewendet, um die iNOS Expression, sowie regulierende Faktoren der iNOS Expression zu bestimmen. Außerdem wurden Methoden etabliert, um den iNOS abhängigen oxidativen Stress zu messen. Die Ergebnisse der Arbeit weisen insbesondere auf die Unterschiede in der iNOS Expression zwischen Tiermodellen und humanem Myokardinfarkt hin. In einer ersten Studie lag der Fokus auf der Bestimmung und Quantifizierung der iNOS mRNA und des iNOS Proteins in postmortalen humanen Infarktherzen. Ein signifikanter Anstieg der iNOS mRNA in infarzierten und nicht infarzierten Regionen, im Vergleich zu gesunden Kontrollherzen wurde festgestellt. Zusätzlich wurde auch ein signifikanter Anstieg des iNOS Proteins in infarzierten und nicht-infarzierten Regionen beobachtet. Hauptsächlich wurden gewebeständige “M2” Makrophagen als die iNOS exprimierenden Zellen im humanen Myokardinfarkt festgestellt, zu einem kleineren Anteil fand sich die iNOS Expression auch in inflammatorischen “M1” Makrophagen. Dementsprechend war der signifikante Anstieg der iNOS Protein Expression in den infarzierten Regionen in den gewebeständigen Makrophagen zu finden. Die Kardiomyozyten wiesen dagegen keine iNOS Expression auf. Abschließend wurde eine Distanzanalyse zwischen iNOS+ und Nitrotyrosin+ Zellen durchgeführt, die einen Höchstwert an Nitrotyrosin+ Zellen im Umkreis von 10-15µm von iNOS exprimierenden Zellen aufwies. Damit ist von einem Aktivitätsradius der iNOS in diesem Umkreis auszugehen und der durch Nitrotyrosin nachgewiesene oxidative Stress möglicherweise auf iNOS zurückzuführen. In einer zweiten Studie wurden micro RNAs (miRNAs) als mögliche posttranskriptionale Regulatoren der iNOS Expression untersucht. In human Hepatozyten ist beschrieben, dass miR-939 die Zytokin-induzierte iNOS Protein Expression, sowie die NO-Synthese verringert. miR-21 ist die am stärksten exprimierte kardiale miRNA und vorranging in kardialen Makrophagen zu finden. Auch in Fibroblasten ist miR-21 exprimiert und reguliert die Proliferation der Fibroblasten. miR-30 ist herunterreguliert in hypoxischen Kardiomyozyten und in Infarktgewebe von Rattenherzen, um das Myokardium u.a. durch ein Inhibieren der Apoptose zu schützen. Die Expressionen von miR-939, miR-21 und miR-30e wurden gemessen und mit iNOS mRNA und Protein Expression korreliert. Die Ergebnisse zeigen eine signifikante Hochregulierung der miR-939, miR-21 und miR-30e in infarzierten und nicht-infarzierten Regionen der postmortalen humanen Infarktherzen im Vergleich zu gesunden Kontrollen. Korrelationsanalysen zeigten eine signfikante Korrelation zwischen miR-939 Expression und der iNOS Genexpression in der Kontrollgruppe und den infarzierten Regionen. In der Kontrollgruppe war die Korrelation stärker ausgeprägt. Eine massive iNOS Aktivierung in den infarzierten Regionen könnte die Kapazität von miR-939 übersteigen, die iNOS Expression in Balance zu halten. miR-21 und miR-30e zeigten keinen Einfluss auf die iNOS Expression oder die Makrophagenpolarisierung. In einer dritten Studie wurde das iNOS Gen NOS2 genotypisiert auf den (CCTTT)n Längenpolymorphismus in der Promotorregion, den rs2779249, G>T Single Nukleotid Polymorphismus (SNP) -1026 Basenpaare (bp) vor Transkriptionsstart und den rs2297518, C>T SNP in Exon 16. Diese Polymorphismen beeinflussen die iNOS Expression und oxidativen Stress u.a. bei Vorhofflimmern und Bluthochdruck. In der Infarktgruppe wurde eine Häufung der NOS2 Risikopolymorphismen, wie längere (CCTTT)n Längenpolymorphismen und T-Allele an den Positionen rs2779249, G>T und rs2297518, C>T im Vergleich zur Kontrollgruppe gefunden. Zusätzlich wurde eine Anstieg an iNOS Protein gefunden, sowohl in der Kontroll- als auch in der Infarktgruppe, wenn NOS2 Risikopolymorphismen vorhanden waren. Serumkonzentrationen von Malondialdehyd (MDA), einem Marker für oxidativen Stress, von Kreatinin, einem unabhängigen Risikofaktor für und nach Myokardinfarkt, und von Nitrat/Nitrit (NOx), die die Aktivität der iNOS reflektieren, waren in der Infarktgruppe erhöht, im Vergleich zur Kontrollgruppe. Des Weiteren hatten homozygote Träger von längeren (CCTTT)n Längenpolymorphismen in der Infarktgruppe höhere Serum MDA Konzentrationen als heterozygote Träger oder homozygote Träger von kürzeren (CCTTT)n Längenpolymorphismen. Homozygote Träger des T-Allels an Position rs2779249, G>T zeigten in der Infarktgruppe erhöhte Serumkonzentrationen von Nitrat und Kreatinin. Das lässt auf einen Zusammenhang zwischen Serummarkern und NOS2 Risikopolymorphismen bei Myokardinfarkt schließen, dennoch wurde kein direkter Einfluss von NOS2 Risikopolymorphismen auf kardiale iNOS Level beobachtet. Zusammenfassend zeigt die vorliegende Doktorarbeit einen signifikanten Anstieg der iNOS Expression in postmortalen humanen Infarktherzen, die vorranging von den gewebeständigen “M2” Makrophagen ausgeht. Außerdem konnte ein Aktivitätsradius der iNOS im Umkreis von 10-15µm detektiert werden, in dem es zu einem Höchstwert an Nitrotyrosin+ Zellen kommt. miR-939 scheint die iNOS Expression posttranskriptional zu regulieren, aber bei Myokardinfarkt übersteigt die iNOS Aktivität den regulatorischen Effekt von miR-939. Des Weiteren gibt es eine Häufung von NOS2 Risikopolymorphismen in der Infarktgruppe, die die iNOS Protein Expression erhöhen. Das kann zu gesteigertem oxidativem Stress und einem kardialen Remodeling nach Myokardinfarkt führen. Die in der Infarktgruppe festgestellten erhöhten Serumkonzentrationen von MDA, Kreatinin und NOx konnten weder mit kardialer iNOS mRNA oder Protein Expression korreliert werden, allerdings scheinen längere (CCTTT)n Längenpolymorphismen und homozygote T Allele an Position rs2779249, G>T die Serummarker zu beeinflussen. Die Rolle der iNOS bei humanem Myokardinfarkt ist komplex, allerdings konnten wir gesteigerten oxidativen Stress im Gewebe nachweisen, der direkt auf die erhöhte iNOS Produktion zurückzuführen ist. Demnach könnte eine erhöhte iNOS Aktivität aufgrund gewisser Risikopolymorphismen den Heilungsprozess nach Myokardinfarkt beeinflussen, zu kardialem Remodeling führen und somit Folgeerkrankungen begünstigen wie eine chronische Herzinsuffizienz.

Deutsch
Status: Verlagsversion
URN: urn:nbn:de:tuda-tuprints-263338
Sachgruppe der Dewey Dezimalklassifikatin (DDC): 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
Fachbereich(e)/-gebiet(e): 10 Fachbereich Biologie
10 Fachbereich Biologie > Molecular Genetics
Hinterlegungsdatum: 21 Nov 2023 13:11
Letzte Änderung: 22 Nov 2023 09:50
PPN:
Referenten: Thiel, Prof. Dr. Gerhard ; Kauferstein, Prof. Dr. Silke ; Galuske, Prof. Dr. Ralf ; Nuber, Prof. Dr. Ulrike
Datum der mündlichen Prüfung / Verteidigung / mdl. Prüfung: 5 Oktober 2023
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