Papers by Germán E. Gonzalez
The FASEB Journal, 2010
We previously reported that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) reduces fibrosis and ... more We previously reported that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) reduces fibrosis and inflammation (macrophages and mast cells). However, it is not known whether Ac-SDKP decreases collagen cross-linking and lymphocyte infiltration; lymphocytes modulate both collagen cross-linking and extracellular matrix formation in hypertension. Thus, we hypothesized that 1) in angiotensin (Ang) II-induced hypertension, Ac-SDKP prevents increases in cross-linked and total collagen by down-regulating lysyl oxidase (LOX), the enzyme responsible for cross-linking, and 2) these effects are associated with decreased a) pro-fibrotic cytokine TGF-β and b) the proinflammatory transcription factor nuclear factor κB (NFκB), and c) CD4+/CD8+ lymphocyte infiltration. We induced hypertension in rats by infusing Ang II either alone or combined with Ac-SDKP for 3 weeks. While Ac-SDKP failed to lower blood pressure or left ventricular hypertrophy, it did prevent Ang II-induced increases in 1) cross-linked and total collagen, 2) LOX mRNA expression and LOXL1 protein, 3) TGF-β expression, 4) nuclear translocation of NFκB, 5) CD4+/ CD8+ lymphocyte infiltration and 6) CD68+ macrophages infiltration. In addition, we found a positive correlation between CD4+ infiltration and LOXL1 expression. In conclusion, the effect of
Experimental Physiology, 2011
Balb/c mice, which are T-helper lymphocyte 2 (Th2) responders, are highly susceptible to infectio... more Balb/c mice, which are T-helper lymphocyte 2 (Th2) responders, are highly susceptible to infectious and non-infectious heart diseases, whereas C57BL/6 mice (Th1 responders) are not. Angiotensin II (Ang II) is not only a vasopressor but also a pro-inflammatory factor that leads to cardiac hypertrophy, fibrosis and dysfunction. We hypothesized that Ang II exacerbates cardiac damage in Balb/c but not in C57BL/6 mice even though both strains have a similar level of hypertension. Twelve-week-old male C57BL/6J and Balb/c mice received either vehicle or Ang II (1.4mg kg −1 day −1 , s.c. via osmotic minipump) for 8 weeks. At baseline, Balb/c mice exhibited the following: (1) a lower heart rate; (2) an enlarged left ventricular chamber; (3) a lower ejection fraction and shortening fraction; and (4) twice the left ventricular collagen deposition of agematched C57BL/6J mice. Angiotensin II raised systolic blood pressure (to ~150 mmHg) and induced cardiomyocyte hypertrophy in a similar manner in both strains. While C57BL/6J mice developed compensatory concentric hypertrophy and fibrosis in response to Ang II, Balb/c mice demonstrated severe left ventricular chamber dilatation, wall thinning and fibrosis, leading to congestive heart failure as evidenced by dramatically decreased ejection fraction and lung congestion (significant increase in lung weight), which are both characteristic of dilated cardiomyopathy. Our study suggests that the Th phenotype plays an active role in cardiac remodelling and function both in basal conditions and in hypertension. Angiotensin II-induced dilated cardiomyopathy in Balb/c mice is an ideal animalmodel for studying the impact of the adaptive immune system on cardiac remodelling and function and for testing strategies to prevent or treat hypertension-associated heart failure. T-helper lymphocytes (Th) are divided into two main subtypes,Th1 andTh2, according to their distinct cytokine profiles (Mosmann et al. 1986; Rogge, 2002). The Th1 cytokines include interleukin-2 and interferon-γ, which suppress Th2 response; while typical Th2 cytokines are interleukin-4 (IL-4) and interleukin-10, which inhibit Th1 (Paul & Seder, 1994). Imbalance of Th1-Th2 plays an important role in the pathophysiology of heart disease (Okura et al. 1998; Shimizu et al. 2004; Yu et al. 2006). Susceptibility to heart disease varies between strains, because each has a distinct immunological phenotype. Autoimmune-and coxsackievirus (Cox) B-induced myocarditis can be induced in Th2
American Journal of Physiology-Heart and Circulatory Physiology, 2009
To characterize the temporal activation of the renin-angiotensin system after myocardial infarcti... more To characterize the temporal activation of the renin-angiotensin system after myocardial infarction (MI) in rabbits, we examined cardiac ANG II type 1 receptor (AT1R) expression and ANG II levels from 3 h to 35 days. The effects of losartan (12.5 mg·kg−1·day−1) on functional and histomorphometric parameters when treatment was initiated early (3 h) and late ( day 15) post-MI and maintained for different periods of time [short term (4 days), midterm (20 days), and long term (35 days)] were also studied. AT1R expression increased in the MI zone at 15 and 35 days ( P < 0.05). ANG II levels increased ( P < 0.05) in the non-MI zone at 24 h and in the MI zone as well as in plasma at 4 days and then progressively decreased until 35 days. The survival rate was significantly lower in untreated MI and early long-term-treated animals. Diastolic pressure-volume curves in MI at 35 and 56 days shifted to the right ( P < 0.05). This shift was even more pronounced in long-term-treated group...
This is the third and last article of a series devoted to Carl Friedrich Wilhelm Ludwig's out... more This is the third and last article of a series devoted to Carl Friedrich Wilhelm Ludwig's outstanding life (29 December 1816–23 April 1895). The first article portrayed him as a bioengineer [1] and the second as a physiologist [2]. Here, we view him as a teacher, the teacher par excellence, as recognized and commended by Theodor Beer (1866–1919)—a naturalist and physiologist who, incidentally, had a disgraced, sad, and ruined life [3]—making it a dramatic history subject, especially for its several human facets and controversial feelings and beliefs. In his own words: Ludwig war der deutsche Professor par excellence, der deutsche Professor im besten Sinne des Wortes, er war nicht nur tüchtig, sondern auch bedeutend, ein Klassiker in seiner Art.Fil: Valentinuzzi, Max E.. Universidad de Buenos Aires. Facultad de Ingeniería; ArgentinaFil: Beneke, Klaus. Christian-AlbrechtsUniversity; AlemaniaFil: González, Germán Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. ...
Argentine Journal of Cardiology, 2015
Background: Galectin-3 (Gal-3) is a lectin that regulates the immune response. However, its role ... more Background: Galectin-3 (Gal-3) is a lectin that regulates the immune response. However, its role in remodeling and ventricular function after myocardial infarction (MI) is unknown. Objective: The purpose of this study was to analyze whether Gal-3 deficit impairs remodeling and ventricular function after MI in mice. Methods: Male Gal-3 KO mice and their respective C57 controls underwent anterior descending coronary artery ligation or sham operation. Animals were then divided into four experimental groups: 1) C57 sham; 2) Gal-3 KO sham; 3) C57 MI and 4) Gal-3 KO MI. Seven days after surgery, an echocardiography was performed followed by euthanasia. Heart samples were collected to measure MI size and fibrosis using Masson’s trichrome and picrosirius red, respectively, and assess macrophage infiltration and IL-6 expression. Results: Left ventricular diameters were significantly increased in the C57 MI group compared with sham animals and the increase was even higher in the Gal-3 KO MI g...
The American Journal of Pathology, 2020
We studied the role of galectin-3 (Gal-3) in the expression of alternative activation markers (M2... more We studied the role of galectin-3 (Gal-3) in the expression of alternative activation markers (M2) on macrophage, cytokines, and fibrosis through the temporal evolution of healing, ventricular remodeling, and function after myocardial infarction (MI). C57BL/6J and Gal-3 knockout mice (Lgals3-/-) were subjected to permanent coronary ligation or sham. We studied i) mortality, ii) macrophage infiltration and expression of markers of alternative activation, iii) cytokine, iv) matrix metalloproteinase-2 activity, v) fibrosis, and vi) cardiac function and remodeling. At 1 week post-MI, lack of Gal-3 markedly attenuated F4/80þ macrophage infiltration and significantly increased the expression of Mrc1 and Chil1, markers of M2 macrophages at the MI zone. Levels of IL-10, IL-6, and matrix metalloproteinase-2 were significantly increased, whereas tumor necrosis factor-a, transforming growth factor-b, and fibrosis were remarkably attenuated at the infarct zone. In Gal-3 knockout mice, scar thinning ratio, expansion, and cardiac remodeling and function were severely affected from the onset of MI. At 4 weeks post-MI, the natural evolution of fibrosis in Gal-3 knockout mice was also affected. Our results suggest that Gal-3 is essential for wound healing because it regulates the dynamics of macrophage infiltration, proinflammatory and anti-inflammatory cytokine expression, and fibrosis along the temporal evolution of MI in mice. The deficit of Gal-3 affected the dynamics of wound healing, thus aggravating the evolution of remodeling and function.
American journal of physiology. Heart and circulatory physiology, Nov 5, 2016
The lectin Galectin-3 (Gal-3) is important in immune regulation. In both hypertensive rats and he... more The lectin Galectin-3 (Gal-3) is important in immune regulation. In both hypertensive rats and heart-failure patients, Gal-3 is also a marker for unfavorable prognosis. Nevertheless, the mechanism of Gal-3 action in hypertension-induced target organ damage is unknown. We hypothesized that in Ang II-induced hypertension, Gal-3 deficiency prevents left ventricular (LV) adverse remodeling and LV dysfunction by reducing immune responses and myocardial fibrosis. Male C57BL/6J and Gal-3 knockout (KO) mice were infused with Ang II for 8 weeks. We assessed: 1) systolic blood pressure (SBP) by plethysmography; 2) LV function and remodeling by echocardiography, 3) myocardial fibrosis by histology, 4) cardiac macrophage infiltration by histology, 5) ICAM-1 and VCAM-1 expression by Western blotting, 6) plasma cytokines by enzyme-linked immunosorbent assay, and 7) regulatory T cells (Treg) by flow cytometry detected by their combined expression of CD4, CD25, and FOXP3. SBP and cardiac hypertroph...
Journal of Hypertension, 2015
Objective-Inflammation has been proposed as a key component in the development of hypertension an... more Objective-Inflammation has been proposed as a key component in the development of hypertension and cardiac remodeling associated with different cardiovascular diseases. However, the role of the proinflammatory cytokine interleukin-6 in the chronic stage of hypertension is not well defined. Here, we tested the hypothesis that deletion of interleukin-6 protects against the development of hypertension, cardiac inflammation, fibrosis, remodeling and dysfunction induced by high salt diet and angiotensin II (Ang II). Methods-Male C57BL/6J and interleukin-6-knock out (KO) mice were implanted with telemetry devices for blood pressure (BP) measurements, fed a 4% NaCl diet, and infused with either vehicle or Ang II (90 ng/min per mouse subcutaneously) for 8 weeks. We studied BP and cardiac function by echocardiography at baseline, 4 and 8 weeks. Results-Myocyte cross-sectional area (MCSA), macrophage infiltration, and myocardial fibrosis were also assessed. BP increased similarly in both strains when treated with Ang II and high salt (Ang II-high salt); however, C57BL/6J mice developed a more severe decrease in left ventricle ejection fraction, fibrosis, and macrophage infiltration compared with interleukin-6-KO mice. No differences between strains were observed in MCSA, capillary density and MCSA to capillary density ratio.
Clinical Science, 2014
We have reported previously that Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) reduces fibrosis... more We have reported previously that Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) reduces fibrosis and inflammation (in macrophages and mast cells). However, it is not known whether Ac-SDKP decreases collagen cross-linking and lymphocyte infiltration; lymphocytes modulate both collagen cross-linking and ECM (extracellular matrix) formation in hypertension. Thus we hypothesized that (i) in AngII (angiotensin II)-induced hypertension, Ac-SDKP prevents increases in cross-linked and total collagen by down-regulating LOX (lysyl oxidase), the enzyme responsible for cross-linking, and (ii) these effects are associated with decreased pro-fibrotic cytokine TGFβ (transforming growth factor β) and the pro-inflammatory transcription factor NF-κB (nuclear factor κB) and CD4+/CD8+ lymphocyte infiltration. We induced hypertension in rats by infusing AngII either alone or combined with Ac-SDKP for 3 weeks. Whereas Ac-SDKP failed to lower BP (blood pressure) or LV (left ventricular) hypertrophy, it d...
Canadian Journal of Physiology and Pharmacology, 2006
The aims of the present study were to determine whether the transitory systolic overshoot (TSO) t... more The aims of the present study were to determine whether the transitory systolic overshoot (TSO) that occurs in the early reperfusion (R) of the stunned myocardium is accompanied by diastolic alterations, and to determine whether the R with low Ca2+ Krebs–Henseleit’s solution or with adenosine modifies these alterations. Isolated–isovolumic rabbit hearts were divided in 3 groups (G). G1 (n = 11) was perfused with…
Journal of Cardiovascular Pharmacology, 2007
The a1-adrenergic receptors (a1-ARs) are involved in preconditioning. Given that certain intracel... more The a1-adrenergic receptors (a1-ARs) are involved in preconditioning. Given that certain intracellular pathways seem to be shared by preconditioning and postconditioning, it is possible that postconditioning could also be mediated by a1-ARs. The objective was to evaluate, by analyzing infarct size, if a1-ARs activation could trigger postconditioning and also determine Akt and glycogen synthase kinase 3b (GSK-3b) phosphorylation. Langendorff-perfused rat hearts were subjected to 30 minutes of ischemia and 120 minutes of reperfusion (I/R; n = 8). After 30 minutes of global ischemia, we performed 6 cycles of reperfusion/ischemia of 10 seconds each, followed by 120 minutes of reperfusion [ischemic postconditioning group (postcon); n = 9]. In another postcon group, we administered prazosin during postcon protocol (postcon + prazosin; n = 7). Finally, we repeated the I/R group, but prazosin (prazosin; n = 7), phenylephrine (PE; n = 5) and clonidine (CL; n = 6) were administered during the first 2 minutes of reperfusion. Infarct size was measured using the triphenyltetrazolium chloride technique. Total and phosphorylated Akt and mitochondrial GSK-3b expression were measured by Western blot. Infarct size was 58.1 6 5.1% in I/R. Postcon and PE reduced infarct size to 40.1 6 2.9% and 35.3 6 5.5%, respectively (P , 0.05 vs. I/R). Postcon + prazosin administration abolished the beneficial effect on infarct size (61.6 6 4.5%; P , 0.05 vs. postcon). Cytosolic Akt phosphorylation and mitochondrial GSK-3b phosphorylation were higher in the postcon and PE groups compared with the I/R and postcon + prazosin groups. Prazosin or clonidine administration did not modify neither protein expression nor infarct size. Our data demonstrate that postconditioning decrease infarct size by activation of the a1-AR pathway through Akt and GSK-3b phosphorylation.
Cellular Physiology and Biochemistry, 2009
Objective: In this study the effect of ribose on heart function and infarct-size was analyzed 6 h... more Objective: In this study the effect of ribose on heart function and infarct-size was analyzed 6 h after myocardial infarction (MI) in rats. Methods: Continuous i.v.-infusion of NaCl or ribose (200 mg/ kg/h) was started one day prior to induction of MI in female Sprague-Dawley rats which was done by ligation of the left coronary artery. Six hours after MI heart function was measured with 3F tip catheter, cardiac output by thermodilution method. Thereafter the ischemic area was delineated by Evans Blue infusion, and the infarct area was visualized by triphenyltetrazolium chloride staining. The mRNA expression of interleukin (IL)-1β, IL-6, matrixmetalloproteinase (MMP)-8, and-9 was measured by ribonuclease protection assay. Results: Heart function was severely depressed 6 hours after coronary artery occlusion, but recovered significantly under the influence of ribose. Left ventricular (LV) systolic pressure (LVSP) and contractility (LVdP/dt max) were restored to the normal levels of sham-operated animals, while parameters of LV relaxation (LVdP/dt min and time constant of relaxation τ) were impaired compared to sham-operated animals, but significantly improved by ribose treatment compared to shamtreated MI-rats. Moreover, the infarct size was significantly smaller in the ribose treated animals despite a comparable ischemic area at risk in all MI-rats. The cytokine mRNA expression after MI was significantly reduced after ribose treatment, while there were no differences regarding MMP expression. Conclusion: MI size was significantly reduced and LV function significantly improved by ribose treatment at 6 h after MI. This seemed to be based on slowing the velocity of the necrotic wave front across the LV wall after MI resulting in smaller infarcts.
Theoretical Biology and Medical Modelling, 2012
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Papers by Germán E. Gonzalez