Biomedical subjects

Maria A Cavasin

Publications and source records attributed to Maria A Cavasin.

10 recordsLinked to original sources

PubMed2006

Therapeutic potential of thymosin-beta4 and its derivative N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) in cardiac healing after infarction.

Despite the numerous advances made in the prevention and treatment of cardiovascular diseases, there is a need for new strategies to repair and/or regenerate the myocardium after ischemia and infarction in order to prevent maladaptive remodeling and cardiac dysfunction. This article compiles and analyzes the available experimental data regarding the potential therapeutic effects of thymosin-beta4 and its derivative N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) in cardiac healing after myocardial infarction (MI) as well as discussing the possible mechanisms involved. The healing properties of thymosin-beta4 have been described in different types of tissues, such as the skin and cornea, and more recently it has been shown that thymosin-beta4 facilitates cardiac repair after infarction by promoting cell migration and myocyte survival. Additionally, the tetrapeptide Ac-SDKP was reported to reduce left ventricular fibrosis in hypertensive rats, reverse fibrosis and inflammation in rats with MI, and stimulate both in vitro and in vivo angiogenesis. Ac-SDKP also reduced cardiac rupture rate in mice post-MI. Some of the effects of Ac-SDKP, such as the enhancement of angiogenesis and the decrease in inflammation and collagenase activity, are similar to those described for thymosin-beta4. Thus, it is possible that Ac-SDKP could be mediating some of the beneficial effects of its precursor. Although the experimental evidence is very promising, there are no data available from a clinical trial supporting the use of thymosin-beta(4) or Ac-SDKP as means of healing the myocardium after MI in patients.

Animals↗

PubMed2005

Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function.

Cardiac rupture can be fatal after myocardial infarction (MI). Experiments in animals revealed gender differences in rupture rate; however, patient data are controversial. We found a significantly higher rupture rate in testosterone-treated female mice within 1 wk after MI, whereas castration in males significantly reduced rupture. We hypothesized that testosterone may adversely affect remodeling after MI, exaggerating the inflammatory response and increasing cardiac rupture, whereas estrogen may be cardioprotective, attenuating early remodeling and reducing rupture rate. We studied the effect of gender and hormone manipulation on morphological and histological changes during early remodeling after MI in 4-wk-old male and female C57BL/6J mice and how these events could affect cardiac function. Females were randomly divided into 1) sham ovariectomy + placebo (s-ovx + P), 2) s-ovx + testosterone (T), 3) ovx + P, and 4) ovx + T; males were divided into 1) sham castration + P (s-cas + P), 2) s-cas + 17beta-estradiol (E), 3) cas + P, and 4) cas + E. At 6 wk after gonadectomy and hormone manipulation, MI was induced. Mice were randomly killed 1, 2, 4, 7, and 14 days after MI. The left ventricle was weighed and sectioned for evaluation of MI size, infarct expansion index (IEI), and neutrophil infiltration. Transthoracic echocardiography was performed in conscious mice in the 14-day group before organ harvest. Cardiac rupture rate and IEI were significantly higher in testosterone-treated females and noncastrated males than in controls; these effects were accompanied by enhanced neutrophil infiltration and pronounced deterioration of cardiac function and left ventricular dilatation. Ovariectomy in females and estrogen supplementation in males did not confer significant protection from cardiac rupture, IEI, or neutrophil infiltration. We concluded that, in mice, high testosterone levels enhance acute myocardial inflammation, adversely affecting myocardial healing and early remodeling, as indicated by increased cardiac rupture, and possibly causing deterioration of cardiac function after MI, and, conversely, estrogen seems to have no significant protective effect in the acute phase after MI.

Animals↗

PubMed2004

Gender differences in cardiac function during early remodeling after acute myocardial infarction in mice.

There are conflicting data about gender differences in cardiac function after myocardial infarction (MI), including cardiac rupture and mortality. Using a mouse model of MI, we recently found that the cardiac rupture rate during the first week after MI was significantly lower in females than in males, suggesting that females have attenuated structural remodeling. Thus in this study, we attempted to determine whether: a) females have attenuated remodeling and faster healing during the early phase post-MI, and b) females have better cardiac function and outcome during the chronic phase compared to males. MI was induced in 12-week-old male and female C57BL/6J mice. Signs of early remodeling, including cardiac rupture, infarct expansion, inflammatory response, and collagen deposition, were studied during the first 2 weeks post-MI. Left ventricular remodeling and function were followed for 12 weeks post-MI. We found that males had a higher rate of cardiac rupture, occurring mainly at 3 to 5 days of MI and associated with a higher infarct expansion index. Neutrophil infiltration at the infarct border was more pronounced in males than females during the first days of MI, which were also characterized by increased MMP activity. However, the number of infiltrating macrophages was significantly higher in females at day 4. During the chronic phase post-MI, males had significantly poorer LV function, more prominent dilatation and significant myocyte hypertrophy compared to females. In conclusion, males have delayed myocardial healing, resulting in cardiac rupture, and the survivors have poorer cardiac function and pronounced maladaptive remodeling, whereas females show a better outcome during the development of HF.

Acute Disease↗

PubMed2004

Prolyl oligopeptidase is involved in release of the antifibrotic peptide Ac-SDKP.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous tetrapeptide hydrolyzed almost exclusively by angiotensin-converting enzyme (ACE). Chronic treatment with Ac-SDKP decreases cardiac and renal fibrosis and inflammatory cell infiltration in hypertensive rats. However, very little is known about endogenous synthesis of Ac-SDKP, except that thymosin-beta4 may be the most likely precursor. Two enzymes are potentially able to release Ac-SDKP from thymosin-beta4: prolyl oligopeptidase (POP) and endoproteinase asp-N. POP is widely present and active in several tissues and biological fluids, whereas endoproteinase asp-N appears to be lacking in mammals. Therefore, we hypothesized that POP is the main enzyme involved in synthesizing the antifibrotic peptide Ac-SDKP. We investigated in vitro and in vivo production of Ac-SDKP. Using kidney cortex homogenates, we observed that Ac-SDKP was generated in a time-dependent manner in the presence of exogenous thymosin-beta4, and this generation was significantly inhibited by several POP inhibitors (POPi), Z-prolyl-prolinal, Fmoc-prolyl-pyrrolidine-2-nitrile, and S17092. Long-term administration of S17092 in rats significantly decreased endogenous levels of Ac-SDKP in the plasma (from 1.76+/-0.2 to 1.01+/-0.1 nM), heart (from 2.31+/-0.21 to 0.83+/-0.09 pmol/mg protein), and kidneys (from 5.62+/-0.34 to 2.86+/-0.76 pmol/mg protein). As expected, ACE inhibitors significantly increased endogenous levels of Ac-SDKP in the plasma, heart, and kidney, whereas coadministration of POPi prevented this increase. We concluded that POP is the main enzyme responsible for synthesis of the antifibrotic peptide Ac-SDKP.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2004

Temporal changes in matrix metalloproteinase expression and inflammatory response associated with cardiac rupture after myocardial infarction in mice.

We previously found that male mice with myocardial infarction (MI) had a high rate of cardiac rupture, which generally occurred at 3 to 5 days after MI. Since matrix metalloproteinases (MMPs) play an important role in infarct healing, tissue repair and extracellular matrix (ECM) remodeling post-MI, we studied the temporal relationship of MMP expression and inflammatory response to cardiac rupture after acute MI. Male C57BL/6J mice were subjected to MI (induced by ligating the left anterior descending coronary artery) and killed 1, 2, 4, 7 or 14 days after MI. MMP-2 and MMP-9 activity in the heart were measured by zymography. Collagen content was measured by hydroxyproline assay. We found that after MI, MMP-9 activity increased as early as 1 day and reached a maximum by 2-4 days, associated with a similar increase in neutrophil and macrophage infiltration in the infarct area. MMP-2 started to increase rapidly within 4 days, reaching a maximum by 7 days and remaining high even at 14 days. Intense macrophage infiltration appeared by 4 days after MI and then gradually decreased within 7 to 14 days. Collagen content was unchanged until 4 days after MI, at which point it increased and remained high thereafter. Our data suggest that in mice, overexpression of MMP-2 and MMP-9 (possibly expressed mainly by neutrophils and macrophages) may lead to excessive ECM degradation in the early phase of MI, impairing infarct healing and aggravating early remodeling which in turn causes cardiac rupture.

Animals↗

PubMed2004

Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension.

OBJECTIVE: N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a potent natural inhibitor of hematopoietic stem cell proliferation which is degraded mainly by angiotensin-converting enzyme (ACE). In vitro, Ac-SDKP inhibits collagen production by cardiac fibroblasts; while in vivo it blocks collagen deposition in the left ventricle (LV) of rats with hypertension or myocardial infarction (MI). In addition, it reportedly prevents and reverses macrophage infiltration in the LV of rats with MI. We tested the hypothesis that when Ac-SDKP is infused at doses that cause plasma concentrations similar to those observed after ACE inhibition, it mimics the anti-inflammatory and antifibrotic effects of ACE inhibitors (ACEi) in the heart, and, further, that these effects are independent of changes in blood pressure. DESIGN AND METHODS: Rats were divided into five groups: (1) controls, (2) Ang II (750 microg/kg per day, s.c.), (3) Ang II + captopril (100 mg/kg per day in drinking water), (4) Ang II + Ac-SDKP (400 microg/kg per day, s.c.), and (5) Ang II + Ac-SDKP (800 microg/kg per day, s.c.). We measured LV cell proliferation, inflammatory cell infiltration, cytokine expression, hypertrophy and fibrosis. RESULTS: Plasma Ac-SDKP was five-fold higher in rats given ACEi and four- and ten-fold higher in rats given 400 and 800 microg/kg per day Ac-SDKP, respectively. ACEi significantly decreased Ang II-induced cell proliferation (Ki-67), LV macrophage/mast cell infiltration, transforming growth factor-beta, connective tissue growth factor and collagen deposition without affecting hypertension, LV hypertrophy or myocyte cross-sectional area, and these effects were mimicked by exogenous Ac-SDKP (400 microg/kg per day) which raised plasma Ac-SDKP to levels similar to ACEi. BP was not decreased by either ACEi or Ac-SDKP. CONCLUSIONS: We concluded that Ac-SDKP may be an important mediator of the anti-inflammatory and antifibrotic effects of ACEi in hypertension independent of its hemodynamic effects.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2004

Role of nitric oxide in the renal hemodynamic response to unilateral nephrectomy.

Reduction of renal mass by unilateral nephrectomy results in an immediate increase in renal blood flow (RBF) to the remnant kidney, followed by compensatory renal hypertrophy. Whether the increase in RBF after unilateral nephrectomy is mediated by nitric oxide (NO) was tested. It was found that immediately after nephrectomy, blood flow to the remaining kidney increased by 8% (P < 0.01), and inhibition of NO synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) blocked the increase in RBF. In addition, 2 d after nephrectomy, there was a 49% increase in RBF (corrected per gram of kidney weight), a 25% increase at 7 and 14 d, and a 16% increase after 28 d. Acute inhibition of NO synthesis with L-NAME in uninephrectomized rats caused a greater decrease in RBF on days 2 and 7 compared with controls, whereas by 14 and 28 d, the response to L-NAME was similar to controls. Urinary excretion of cyclic guanosine monophosphate, a marker for renal NO production, increased 2.5-fold by 2 d after uninephrectomy (P < 0.005) and remained at this level through 28 d. Pretreating rats chronically with a subpressor dose of L-NAME beginning 2 d before nephrectomy blocked the increase in RBF seen at 2 and 7 d and retarded the renal hypertrophy that should have developed by 7 d. It is concluded that after unilateral nephrectomy, immediate and sustained increases in RBF are mediated at least in part by NO. The hypertrophic response to unilateral nephrectomy may be partially initiated by the signal of hemodynamic changes.

Animals↗

PubMed2003

Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction.

Premenopausal women are much less prone to develop cardiovascular disease than men of similar age, but this advantage no longer applies after menopause. We previously found that male mice have a significantly higher rate of cardiac rupture than females during the acute phase of myocardial infarction (MI); however, the effects of sexual hormones on chronic remodeling are unknown. We hypothesized that estrogen (E) may protect the heart from chronic remodeling and deterioration of function post-MI, whereas testosterone (T) may have adverse effects. Mice (4 wk old) of both genders were divided into four groups: female groups consisted of 1) sham ovariectomy (S-Ovx) + placebo (P) (S-Ovx + P), 2) S-Ovx + T, 3) Ovx + P, and 4) Ovx + T; and male groups consisted of 1) sham castration (S-Cas)+ P (S-Cas + P), 2) S-Cas + 17beta-estradiol (E), 3) Cas + P, and 4) Cas + E. MI was induced 6 wk later. Echocardiography was performed to assess cardiac function and left ventricular dimensions (LVD). Myocyte cross-sectional area (MCSA) was measured at the end of the study. In females, both testosterone and ovariectomy decreased ejection fraction (EF) and increased LVD, and when combined they aggravated cardiac function and remodeling further. Testosterone significantly increased MCSA. In males, castration or estrogen increased EF and reduced LVD, whereas castration significantly reduced MCSA. Our data suggest that estrogen prevents deterioration of cardiac function and remodeling after MI, but testosterone worsens cardiac dysfunction and remodeling and has a pronounced effect when estrogen levels are reduced.

Animals↗

PubMed2003

Increased systolic performance with diastolic dysfunction in adult spontaneously hypertensive rats.

Hypertensive heart disease is characterized by early development of hypertrophy and fibrosis that leads to heart failure (HF). HF develops in spontaneously hypertensive rats (SHR) after 18 months; however, it is not clear whether hypertrophy leads to altered cardiac performance at an earlier age in these rats. We studied cardiac performance in 10- to 11-month-old SHR and age-matched Wistar-Kyoto rats (WKY), using presssure-volume (PV) conductance catheter system to evaluate systolic and diastolic function in vivo at different preloads, including preload recruitable stroke work (PRSW), +dP/dt, and its relation to end-diastolic volume (+dP/dt-EDV) and preload-adjusted maximal power (PWR(max)-EDV(2)) as well as the time constant of left ventricular pressure decay, tau (tau), as an index of relaxation. The slope of the end-diastolic pressure-volume relation (EDPVR) and the ex vivo PV relation, both indexes of stiffness, were also calculated for each heart, and the Doppler E/A ratio was determined. In addition, plasma samples were obtained to assess B-type natriuretic peptide levels (BNP). We found that PRSW was higher in SHR than in WKY (174.5+/-15.6 versus 92.6+/-18.9 mm Hg; P<0.01). +dP/dt and +dP/dt-EDV were also enhanced in SHR versus WKY (9125+/-662 versus 6633+/-392 mm Hg/sec, P<0.01, and 28.14+/-4.35 versus 12.7+/-2.8 mm Hg/s per micro L, P<0.02). In addition, PWR-EDV(2) was elevated in SHR (7.3+/-1.5 versus 3.1+/-0.6 mW/ micro L(2)). Tau was prolonged in SHR (14.5+/-1 ms versus 10.8+/-0.8 for WKY, P<0.02) and EDPVR was significantly greater in SHR than in WKY (0.01+/-0.005 versus 0.004+/-0.001, P<0.05). The ex vivo pressure-volume relation was also steeper for SHR and the E/A ratio was 2.53+/-0.15 for SHR versus 1.67+/-0.08 for WKY (P<0.02). BNP was 45+/-2.5 pg/mL for SHR and 33.3+/-1.8 pg/mL for WKY (P<0.02). Taken together, these data suggest that at 10 to 11 months of age, before HF develops, SHR have increased systolic performance accompanied by delayed relaxation and increased diastolic stiffness.

Animals↗

PubMed2002

Long-term effects of selective and nonselective endothelin receptor antagonists in mice with heart failure.

BACKGROUND: The ET(A) and ET(B) receptors mediate vasoconstriction, aldosterone release, and fibrosis. However, the role of ET(B) receptors is still controversial because those expressed on endothelial cells also stimulate vasodilatation and may oppose the actions of the ET(A) receptor. Plasma levels of endothelin-1 (ET-1) are increased in heart failure (HF) and are associated with myocardial dysfunction. The relative efficacy of selective and nonselective ET antagonists in the treatment of HF is unclear. We hypothesized that blockade of ET(A) receptors may improve cardiac function and prevent left ventricular remodeling in mice with HF, and these effects may be mediated in part by activation of ET(B). METHODS AND RESULTS: A mouse model of chronic HF induced by myocardial infarction (MI) was used. Seven days after MI, mice were divided into vehicle, ET(A)-ant, or ET(A/B)-ant groups and treated for 23 weeks. Cardiac function, LV dimensions, and hemodynamics were evaluated in conscious mice before MI and during treatment. Histologic analysis of the heart and liver was performed at the end of the study. HF significantly decreased EF and increased LV dimensions, interstitial collagen fraction (ICF) and myocyte cross-sectional area (MCSA). Both ET(A)-ant and ET(A/B)-ant slightly increased EF but had no significant effect on LV dimensions, hypertrophy, or ICF. Both treatments decreased MCSA; however, this was only significant in the ET(A/B)-ant group. CONCLUSIONS: Both selective and nonselective ET-ant have similar slight effects on cardiac function and remodeling. This suggests that (1) ET(B) receptors do not mediate the beneficial cardiac effects of ET(A)-ant and (2) blockade of the ET system alone may not provide significant cardioprotection, at least in mice with HF induced by MI.

Animals↗