Rainer DeMartin

Bio: Rainer DeMartin is an academic researcher from Medical University of Vienna. The author has contributed to research in topics: Ventricular remodeling & Systole. The author has an hindex of 2, co-authored 2 publications receiving 72 citations.

Inflammation and postinfarct remodeling: Overexpression of IκB prevents ventricular dilation via increasing TIMP levels

Abstract: Objective: Nuclear factor-kappa B (NF-κB) orchestrates genes involved in inflammation and extracellular matrix (ECM) remodeling following myocardial infarction (MI). The objective of the present study was to investigate the effect of overexpression and mode of function of IκB, the natural inhibitor of NF-κB, on ECM remodeling in a rat model of MI. Methods: MI was induced in male Sprague-Dawley rats by ligation of the left anterior descending coronary artery (LAD) and was followed by adenovirus-mediated intramyocardial transfection of IκB ( n =26) or LacZ reporter genes ( n =26). Sham-operated animals ( n =14) served as controls. Results: In transthoracic echocardiography 49 days after MI, systolic and diastolic left ventricular dimensions were reduced while fractional shortening was preserved in the treatment group. Additionally, evaluation on the isolated heart showed an attenuated downward shift of pressure–volume relationships in the IκB group compared to LacZ. NF-κB p65 DNA binding activity was diminished both at 5 and 49 days post-MI in the treatment group. Five days post-MI in the treatment group, protein levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were significantly reduced by 72.6% and 73.2%, respectively, compared to LacZ ( p <0.05). In parallel, matrix metalloproteinase (MMP)-2 and MMP-9 levels were reduced 5 days post-MI, with MMP-9 still being decreased 49 days post-MI ( p <0.01). In contrast, tissue inhibitors of metalloproteinases (TIMP)-1, -2, and -3 were increased compared to LacZ ( p <0.01 and p <0.05, respectively) 5 days post-MI. After 49 days, TIMP-2, -3, and -4 expressions were significantly elevated ( p <0.05). Conclusion: Reducing NF-κB activity via IκB overexpression after MI positively influences ECM remodeling by reducing MMP-2 and -9 levels while increasing TIMP-1, -2, -3, and -4 levels. Therefore, IκB overexpression prevents ventricular dilation and consequently preserves cardiac function.

Adenovirus-mediated overexpression of inhibitor kappa B-alpha attenuates postinfarct remodeling in the rat heart.

Abstract: OBJECTIVE The transcription factor nuclear factor kappa B (NF-kB) plays an important role in the inflammatory response following myocardial infarction We hypothesized that NF-kB-blockade in an animal model of acute ischemia reduces the inflammatory response and therefore attenuates ventricular remodeling METHODS Myocardial infarcts (MI) were produced in male Sprague-Dawley rats by ligation of the LAD and followed by adenovirus-mediated intramyocardial delivery of inhibitor kappa Balpha-gene (n=10), the physiological inhibitor of the transcription factor nuclear factor kappa B, respectively, of a beta-gal reporter-gene (n=11) Sham-operated animals (n=10) received neither ligation nor gene transfer Five days after MI IkB-expression levels were determined by western blotting Seven weeks after MI in vivo cardiac function was evaluated by transthoracic echocardiography Based on left ventricular endsystolic and enddiastolic diameters ejection fraction and fractional shortening were calculated Only animals with MI involving more than 30% of the left ventricle were included Data are given as mean+/-SD RESULTS In IkBalpha-transfected hearts IkBalpha-levels were six-fold higher (P<005) than in beta-gal transfected hearts Concerning in vivo hemodynamics IkBalpha-treated hearts showed reduced systolic and diastolic left ventricular dimensions compared to the beta-gal MI-group (systolic 48+/-4 vs 66+/-3 mm; diastolic 67+/-5 vs 84+/-6 mm; P<001) Consequently fractional shortening (278+/-15 vs 204+/-40%; P<001) and ejection fraction (634+/-36 vs 491+/-83%; P<005) were preserved in IkBalpha hearts compared to beta-gal MI-hearts CONCLUSION It can be concluded that overexpression of IkBalpha leads to an improved cardiac function thereby attenuating postinfarct remodeling

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

Abstract: In adult mammals, massive sudden loss of cardiomyocytes after infarction overwhelms the limited regenerative capacity of the myocardium, resulting in the formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of proinflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/ chemokine (C-C motif) ligand 2 [CCL2]). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin–angiotensin–aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response after myocardial infarction. Dysregulation of immune pathways, impaired suppression of postinfarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.

Role of peroxynitrite in the redox regulation of cell signal transduction pathways.

Abstract: Peroxynitrite is a potent oxidant and nitrating species formed from the reaction between the free radicals nitric oxide and superoxide. An excessive formation of peroxynitrite represents an important mechanism contributing to cell death and dysfunction in multiple cardiovascular pathologies, such as myocardial infarction, heart failure and atherosclerosis. Whereas initial works focused on direct oxidative biomolecular damage as the main route of peroxynitrite toxicity, more recent evidence, mainly obtained in vitro, indicates that peroxynitrite also behaves as a potent modulator of various cell signal transduction pathways. Due to its ability to nitrate tyrosine residues, peroxynitrite affects cellular processes dependent on tyrosine phosphorylation. Peroxynitrite also exerts complex effects on the activity of various kinases and phosphatases, resulting in the up- or downregulation of signalling cascades, in a concentration- and cell-dependent manner. Such roles of peroxynitrite in the redox regulation of key signalling pathways for cardiovascular homeostasis, including protein kinase B and C, the MAP kinases, Nuclear Factor Kappa B, as well as signalling dependent on insulin and the sympatho-adrenergic system are presented in detail in this review.

TNF-α-induced mitochondrial oxidative stress and cardiac dysfunction : restoration by superoxide dismutase mimetic Tempol

Abstract: Mitochondria are indispensable for bioenergetics and for the regulation of physiological/signaling events in cellular life. Although TNF-α-induced oxidative stress and mitochondrial dysfunction are...

Inhibition of NF-κB improves left ventricular remodeling and cardiac dysfunction after myocardial infarction

Abstract: Several studies have demonstrated that NF-κB is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-κB is effectiv...