Volcanic Ash as a Precursor for SARS-CoV-2 Infection Among Susceptible Populations in Ecuador: A Satellite Imaging and Excess Mortality-Based Analysis.

The global coronavirus disease 2019 (COVID-19) pandemic has altered entire nations and their health systems. The greatest impact of the pandemic has been seen among vulnerable populations, such as those with comorbidities like heart diseases, kidney failure, obesity, or those with worse health determinants such as unemployment and poverty. In the current study, we are proposing previous exposure to fine-grained volcanic ashes as a risk factor for developing COVID-19. Based on several previous studies it has been known since the mid 1980s of the past century that volcanic ash is most likely an accelerating factor to suffer from different types of cancer, including lung or thyroid cancer. Our study postulates, that people who are most likely to be infected during a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) widespread wave will be those with comorbidities that are related to previous exposure to volcanic ashes. We have explored 8703 satellite images from the past 21 y of available data from the National Oceanic and Atmospheric Administration (NOAA) database and correlated them with the data from the national institute of health statistics in Ecuador. Additionally, we provide more realistic numbers of fatalities due to the virus based on excess mortality data of 2020-2021, when compared with previous years. This study would be a very first of its kind combining social and spatial distribution of COVID-19 infections and volcanic ash distribution. The results and implications of our study will also help countries to identify such aforementioned vulnerable parts of the society, if the given geodynamic and volcanic settings are similar.

Silver nanoparticles as a potential treatment against SARS-CoV-2: A review.

Several human coronaviruses (HCoVs) are distinguished by the ability to generate epidemics or pandemics, with their corresponding diseases characterized by severe respiratory illness, such as that which occurs in severe acute respiratory syndrome (SARS-CoV), Middle East respiratory syndrome (MERS-CoV), and, today, in SARS-CoV-2, an outbreak that has struck explosively and uncontrollably beginning in December 2019 and has claimed the lives of more than 1.9 M people worldwide as of January 2021. The development of vaccines has taken one year, which is why it is necessary to investigate whether some already-existing alternatives that have been successfully developed in recent years can mitigate the pandemic's advance. Silver nanoparticles (AgNPs) have proved effective in antiviral action. Thus, in this review, several in vitro and in vivo studies of the effect of AgNPs on viruses that cause respiratory diseases are analyzed and discussed to promote an understanding of the possible interaction of AgNPs with SARS-CoV-2. The study focuses on several in vivo toxicological studies of AgNPs and a dose extrapolation to humans to determine the chief avenue of exposure. It can be concluded that the use of AgNPs as a possible treatment for SARS-CoV-2 could be viable, based on comparing the virus' behavior to that of similar viruses in in vivo studies, and that the suggested route of administration in terms of least degree of adverse effects is inhalation. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Loss of Protease-Activated Receptor 4 Prevents Inflammation Resolution and Predisposes the Heart to Cardiac Rupture After Myocardial Infarction.

BACKGROUND: Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial. METHODS: We analyzed protease-activated receptor 4 (Par4) expression in mouse hearts with MI and investigated the effects of Par4 deletion on cardiac remodeling and function after MI by echocardiography, quantitative immunohistochemistry, and flow cytometry. RESULTS: Par4 mRNA and protein levels were increased in mouse hearts after MI and in isolated cardiomyocytes in response to hypertrophic and inflammatory stimuli. Par4-deficient mice showed less myocyte apoptosis, reduced infarct size, and improved functional recovery after acute MI relative to wild-type (WT). Conversely, Par4-/- mice showed impaired cardiac function, greater rates of myocardial rupture, and increased mortality after chronic MI relative to WT. Pathological evaluation of hearts from Par4-/- mice demonstrated a greater infarct expansion, increased cardiac hemorrhage, and delayed neutrophil accumulation, which resulted in impaired post-MI healing compared with WT. Par4 deficiency also attenuated neutrophil apoptosis in vitro and after MI in vivo and impaired inflammation resolution in infarcted myocardium. Transfer of Par4-/- neutrophils, but not of Par4-/- platelets, in WT recipient mice delayed inflammation resolution, increased cardiac hemorrhage, and enhanced cardiac dysfunction. In parallel, adoptive transfer of WT neutrophils into Par4-/- mice restored inflammation resolution, reduced cardiac rupture incidence, and improved cardiac function after MI. CONCLUSIONS: These findings reveal essential roles of Par4 in neutrophil apoptosis and inflammation resolution during myocardial healing and point to Par4 inhibition as a potential therapy that should be limited to the acute phases of ischemic insult and avoided for long-term treatment after MI.

COVID-19: Pandemic in Ecuador: a health disparities perspective / COVID-19: pandemia en Ecuador desde una perspectiva de las disparidades de salud

ABSTRACT The global COVID-19 pandemic initiated in Ecuador with the patient zero in February 2020 and since more than 40,000 persons have been tested positive to the virus, leaving some 3,500 deceased, while approximately about 10,500 persons above annual average numbers died within March to May. A strict lockdown was applied by mid-March, which resulted to a severe economic crisis in the country. Although during the lockdown occurred a notable decrease in the number of new cases, the spread of the infection was already massive, untechnical, political and economic decisions will certainly lead to continuous wave of infections for months. Objective Our study postulates, that persons who are most likely to be infected during such secondary wave will be people who have already health issues to which we count besides the known ones, especially those who are already suffer by the distribution of volcanic ashes, as such pyroclastic material is known to affect lunges and thyroids. Methods A descriptive ecological study of information related to COVID-19 infection at a national level using official data from the Minister of Public Health and volcanic ash fall by geographical area in Ecuador. Results The mortality rate per canton indicated that those with lower attack rates are the ones with highest mortality rate. For instance, Portovelo (21.3/100,000), Playas (18.4/100,000), Santa Rosa (15.8/100,000), Suscal (15.3/100,000) and Penipe (14.3/100,000) reported the highest mortality rate per 100,000 people. The main distribution of such volcanic material is within the central to northern area of the Highlands and Inter-Andean Valley of Ecuador, due to the analysis of some 7394 satellite images of the last 21 years. Conclusions We conclude that areas with high vulnerabilities are also most susceptible to develop COVID-19. Such areas with their respective populations will be affected above average and shall be protected in particular within the presently starting during possible second wave of infection.(AU)

RESUMEN La pandemia de COVID-19 inició en Ecuador en febrero de 2020. Desde el inicio más de 40 000 personas han sido oficialmente diagnosticadas con el virus, que ha dejado al menos 3 500 fallecidas, mientras que aproximadamente unas 10 500 personas por encima del promedio anual murieron entre marzo y mayo de 2020. A mediados de marzo se aplicó el confinamiento absoluto en el país, lo que provocó una grave crisis económica y social en Ecuador. Aunque el bloqueo produjo una reducción en el número de casos, la infección estaba propagada ya entre la comunidad y los diagnósticos aumentaron notable debido a decisiones políticas y económicas, que, sin lugar a duda, conducirán a oleadas posteriores de infección por incluso meses. Objetivo Nuestro estudio postula que las personas que tienen más probabilidades de infectarse durante dicha ola secundaria serán las personas que ya tengan problemas de salud. A la vez, proponemos que aquellos pobladores que ya están sufriendo por la caída de cenizas volcánicas y flujos piroclásticos pueden tener más riesgo tal como lo describimos en casos relacionados con cáncer de tiroides y ceniza. Métodos Es un estudio ecológico descriptivo de la información relacionada con la infección por COVID-19 a nivel nacional, utilizando datos oficiales de contagio del Ministerio de Salud Pública y caída de cenizas volcánicas por área geográfica en Ecuador. Resultados La tasa de mortalidad por cantón indicó que aquellos con tasas de ataque más bajas son los que tienen la tasa de mortalidad más alta. Por ejemplo, Portovelo (21,3 / 100.000), Playas (18,4 / 100.000), Santa Rosa (15,8 / 100 000), Suscal (15,3 / 100 000) y Penipe (14,3 / 100 000) registraron la tasa de mortalidad más alta por cada 100 000 personas. La principal distribución de dicho material volcánico se encuentra dentro de la zona centro-norte de la Sierra y Valle Interandino del Ecuador, debido al análisis de unas 7 394 imágenes satelitales de los últimos 21 años. Conclusiones Concluimos que las áreas con alta vulnerabilidad también son más susceptibles a desarrollar COVID-19. Tales áreas con sus respectivas poblaciones se verán afectadas por encima de la media y estarán protegidas, en particular, dentro del inicio actual durante una posible segunda ola de infección.(AU)

COVID-19: Pandemic in Ecuador: a health disparities perspective.

BACKGROUND: The global COVID-19 pandemic initiated in Ecuador with the patient zero in February 2020 and since more than 40,000 persons have been tested positive to the virus, leaving some 3,500 deceased, while approximately about 10,500 persons above annual average numbers died within March to May. A strict lockdown was applied by mid-March, which resulted to a severe economic crisis in the country. Although during the lockdown. OBJECTIVE: Our study postulates, that persons who are most likely to be infected during such secondary wave will be people who have already health issues to which we count besides the known ones, especially those who are already suffer by the distribution of volcanic ashes, as such pyroclastic material is known to affect lunges and thyroids. occurred a notable decrease in the number of new cases, the spread of the infection was already massive, untechnical, political and economic decisions will certainly lead to continuous wave of infections for months. METHODS: A descriptive ecological study of information related to COVID-19 infection at a national level using official data from the Minister of Public Health and volcanic ash fall by geographical area in Ecuador. RESULTS: The mortality rate per canton indicated that those with lower attack rates are the ones with highest mortality rate. For instance, Portovelo (21.3/100,000), Playas (18.4/100,000), Santa Rosa (15.8/100,000), Suscal (15.3/100,000) and Penipe (14.3/100,000) reported the highest mortality rate per 100,000 people. The main distribution of such volcanic material is within the central to northern area of the Highlands and Inter-Andean Valley of Ecuador, due to the analysis of some 7394 satellite images of the last 21 years. CONCLUSIONS: We conclude that areas with high vulnerabilities are also most susceptible to develop COVID-19. Such areas with their respective populations will be affected above average and shall be protected in particular within the presently starting during possible second wave of infection.

In vitro evaluation of silver nanoparticles cytotoxicity on Hepatic cancer (Hep-G2) cell line and their antioxidant activity: Green approach for fabrication and application.

In this article, biosynthesis of silver nanoparticles (AgNPs) using Andean Mora (Rubus glaucus Benth.) leaf has been reported. Different analytical techniques including UV-vis spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM) and X-ray diffraction (XRD) were used for the characterization of AgNPs. The initial appearance of color change with the intense surface plasmon resonance (SPR) bands around 440-455 in UV-visible spectra revealing the formation of AgNPs. The TEM image showed the AgNPs to be anisotropic, quasi-spherical in shape with sizes in the range of 12-50nm. On the other hand, XRD studies revealed the formation of face-centered cubic structure for AgNPs. The surface modified AgNPs showed no cytotoxicity at the concentration ranging from 0.01µM to 1.0µM on the Hepatic cancer (Hep-G2) cell line and observed antioxidant efficacy >70% at the concentration 0.05mM/0.20mL against 1, 1-diphenyl-2-picrylhydrazyl. From the results obtained it is suggested that AgNPs could be used effectively in future drug delivery systems and other biomedical concerns.

Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system.

Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca(2+) handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca(2+) handling and inhibition of the cardiac renin-angiotensin system.

c-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia.

BACKGROUND: The proto-oncogene Casitas b-lineage lymphoma (c-Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor and nonreceptor tyrosine kinases, resulting in their ubiquitination and downregulation. However, the function of c-Cbl in the control of cardiac function is currently unknown. In this study, we examined the role of c-Cbl in myocyte death and cardiac function after myocardial ischemia. METHODS AND RESULTS: We show increased c-Cbl expression in human ischemic and dilated cardiomyopathy hearts and in response to pathological stress stimuli in mice. c-Cbl-deficient mice demonstrated a more robust functional recovery after myocardial ischemia/reperfusion injury and significantly reduced myocyte apoptosis and improved cardiac function. Ubiquitination and downregulation of key survival c-Cbl targets, epidermal growth factor receptors and focal adhesion kinase, were significantly reduced in c-Cbl knockout mice. Inhibition of c-Cbl expression or its ubiquitin ligase activity in cardiac myocytes offered protection against H2O2 stress. Interestingly, c-Cbl deletion reduced the risk of death and increased cardiac functional recovery after chronic myocardial ischemia. This beneficial effect of c-Cbl deletion was associated with enhanced neoangiogenesis and increased expression of vascular endothelial growth factor-a and vascular endothelial growth factor receptor type 2 in the infarcted region. CONCLUSIONS: c-Cbl activation promotes myocyte apoptosis, inhibits angiogenesis, and causes adverse cardiac remodeling after myocardial infarction. These findings point to c-Cbl as a potential therapeutic target for the maintenance of cardiac function and remodeling after myocardial ischemia.

Angiotensin type 1a receptor-deficient mice develop diabetes-induced cardiac dysfunction, which is prevented by renin-angiotensin system inhibitors.

BACKGROUND: Diabetes-induced organ damage is significantly associated with the activation of the renin-angiotensin system (RAS). Recently, several studies have demonstrated a change in the RAS from an extracellular to an intracellular system, in several cell types, in response to high ambient glucose levels. In cardiac myocytes, intracellular angiotensin (ANG) II synthesis and actions are ACE and AT1 independent, respectively. However, a role of this system in diabetes-induced organ damage is not clear. METHODS: To determine a role of the intracellular ANG II in diabetic cardiomyopathy, we induced diabetes using streptozotocin in AT1a receptor deficient (AT1a-KO) mice to exclude any effects of extracellular ANG II. Further, diabetic animals were treated with a renin inhibitor aliskiren, an ACE inhibitor benazeprilat, and an AT1 receptor blocker valsartan. RESULTS: AT1a-KO mice developed significant diastolic and systolic dysfunction following 10 wks of diabetes, as determined by echocardiography. All three drugs prevented the development of cardiac dysfunction in these animals, without affecting blood pressure or glucose levels. A significant down regulation of components of the kallikrein-kinin system (KKS) was observed in diabetic animals, which was largely prevented by benazeprilat and valsartan, while aliskiren normalized kininogen expression. CONCLUSIONS: These data indicated that the AT1a receptor, thus extracellular ANG II, are not required for the development of diabetic cardiomyopathy. The KKS might contribute to the beneficial effects of benazeprilat and valsartan in diabetic cardiomyopathy. A role of intracellular ANG II is suggested by the inhibitory effects of aliskiren, which needs confirmation in future studies.

Direct renin inhibition prevents cardiac dysfunction in a diabetic mouse model: comparison with an angiotensin receptor antagonist and angiotensin-converting enzyme inhibitor.

Hyperglycaemia up-regulates intracellular AngII (angiotensin II) production in cardiac myocytes, effects of which are blocked more effectively by renin inhibition than ARBs (angiotensin receptor blockers) or ACEis (angiotensin-converting enzyme inhibitors). In the present study, we determined whether renin inhibition is more effective at preventing diabetic cardiomyopathy than an ARB or ACEi. Diabetes was induced in adult mice for 10 weeks by STZ (streptozotocin). Diabetic mice were treated with insulin, aliskiren (a renin inhibitor), benazeprilat (an ACEi) or valsartan (an ARB) via subcutaneous mini-pumps. Significant impairment in diastolic and systolic cardiac functions was observed in diabetic mice, which was completely prevented by all three RAS (renin-angiotensin system) inhibitors. Hyperglycaemia significantly increased cardiac oxidative stress and circulating inflammatory cytokines, which were blocked by aliskiren and benazeprilat, whereas valsartan was partially effective. Diabetes increased cardiac PRR (prorenin receptor) expression and nuclear translocation of PLZF (promyelocytic zinc finger protein), which was completely prevented by aliskiren and valsartan, and partially by benazeprilat. Renin inhibition provided similar protection of cardiac function to ARBs and ACEis. Activation of PLZF by PRR represented a novel mechanism in diabetic cardiomyopathy. Differential effects of the three agents on oxidative stress, cytokines and PRR expression suggested subtle differences in their mechanisms of action.

Beta1-adrenergic receptors promote focal adhesion signaling downregulation and myocyte apoptosis in acute volume overload.

Numerous studies demonstrated increased expression of extracellular matrix (ECM) proteins and activation of focal adhesion (FA) signaling pathways in models of pressure overload-induced cardiac hypertrophy. However, little is known about FA signaling in response to volume overload where cardiac hypertrophy is associated with ECM loss. This study examines the role of beta1-adrenergic receptors (ß(1)-ARs) in FA signaling changes and myocyte apoptosis induced during acute hemodynamic stress of volume overload. Rats with eccentric cardiac hypertrophy induced after aorto-caval fistula (ACF) develop reduced interstitial collagen content and decreased tyrosine phosphorylation of key FA signaling molecules FAK, Pyk(2) and paxillin along with an increase in cardiac myocyte apoptosis. ACF also increased activation of PTEN, a dual lipid and protein phosphatase, and its interaction with FA proteins. ß(1)-AR blockade (extended-release of metoprolol succinate, 100mg QD) markedly attenuated PTEN activation, restored FA signaling and reduced myocyte apoptosis induced by ACF at 2days, but failed to reduce interstitial collagen loss and left ventricular dilatation. Treating cultured myocytes with ß(1)-AR agonists or adenoviral expression of ß(1)-ARs caused PTEN activation and interaction with FA proteins, thus leading to FA signaling downregulation and myocyte apoptosis. Adenoviral-mediated expression of a catalytically inactive PTEN mutant or wild-type FAK restored FA signaling downregulation and attenuated myocyte apoptosis induced by ß(1)-ARs. Collectively, these data show that ß(1)-AR stimulation in response to ACF induces FA signaling downregulation through an ECM-independent mechanism. This effect involves PTEN activation and may contribute to adverse cardiac remodeling and function in the course of volume overload.

Cardiac-specific genetic inhibition of nuclear factor-κB prevents right ventricular hypertrophy induced by monocrotaline.

Uncontrolled pulmonary arterial hypertension (PAH) results in right ventricular (RV) hypertrophy (RVH), progressive RV failure, and low cardiac output leading to increased morbidity and mortality (McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. J Am Coll Cardiol 53: 1573-1619, 2009). Although the exact figures of its prevalence are difficult to obtain because of the diversity of identifiable causes, it is estimated that the incidence of pulmonary hypertension is seven to nine cases per million persons in the general population and is most prevalent in the age group of 20-40, occurring more commonly in women than in men (ratio: 1.7 to 1; Rubin LJ. N Engl J Med 336: 111-117, 1997). PAH is characterized by dyspnea, chest pain, and syncope. Unfortunately, there is no cure for this disease and medical regimens are limited (Simon MA. Curr Opin Crit Care 16: 237-243, 2010). PAH leads to adverse remodeling that results in RVH, progressive right heart failure, low cardiac output, and ultimately death if left untreated (Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. J Am Coll Cardiol 43: 13S-24S, 2004; Humbert M, Sitbon O, Simonneau G. N Engl J Med 351: 1425-1436, 2004. LaRaia AV, Waxman AB. South Med J 100: 393-399, 2007). As there are no direct tools to assess the onset and progression of PAH and RVH, the disease is often detected in later stages marked by full-blown RVH, with the outcome predominantly determined by the level of increased afterload (D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Ann Intern Med 115: 343-349, 1991; Sandoval J, Bauerle O, Palomar A, Gomez A, Martinez-Guerra ML, Beltran M, Guerrero ML. Validation of a prognostic equation Circulation 89: 1733-1744, 1994). Various studies have been performed to assess the genetic, biochemical, and morphological components that contribute to PAH. Despite major advances in the understanding of the pathogenesis of PAH, the molecular mechanism(s) by which PAH promotes RVH and cardiac failure still remains elusive. Of all the mechanisms involved in the pathogenesis, inflammation and oxidative stress remain the core of the etiology of PAH that leads to development of RVH (Dorfmüller P, Perros F, Balabanian K, Humbert M. Eur Respir J 22: 358-363, 2003).

Inhibition of nuclear factor κB regresses cardiac hypertrophy by modulating the expression of extracellular matrix and adhesion molecules.

Myocardial remodeling denotes a chronic pathological condition of dysfunctional myocardium that occurs in cardiac hypertrophy (CH) and heart failure (HF). Reactive oxygen species (ROS) are major initiators of excessive collagen and fibronectin deposition in cardiac fibrosis. Increased production of ROS and nuclear factor κB (NF-κB) activation provide a strong link between oxidative stress and extracellular matrix (ECM) remodeling in cardiac hypertrophy. The protective inhibitory actions of pyrrolidine dithiocarbamate (PDTC), a pharmacological inhibitor of NF-κB and a potent antioxidant, make this a good agent to evaluate the role of inhibition of NF-κB and prevention of excessive ECM deposition in maladaptive cardiac remodeling during HF. In this report, we used a transgenic mouse model (Myo-Tg) that has cardiac-specific overexpression of myotrophin. This overexpression of myotrophin in the Myo-Tg model directs ECM deposition and increased NF-κB activity, which result in CH and ultimately HF. Using the Myo-Tg model, our data showed upregulation of profibrotic genes (including collagen types I and III, connective tissue growth factor, and fibronectin) in Myo-Tg mice, compared to wild-type mice, during the progression of CH. Pharmacological inhibition of NF-κB by PDTC in the Myo-Tg mice resulted in a significant reduction in cardiac mass, NF-κB activity, and profibrotic gene expression and improved cardiac function. To the best of our knowledge, this is the first report of ECM regulation by inhibition of NF-κB activation by PDTC. The study highlights the importance of the NF-κB signaling pathway and therapeutic benefits of PDTC treatment in cardiac remodeling.

Pleiotropic effects of neutrophils on myocyte apoptosis and left ventricular remodeling during early volume overload.

Most of the available evidence on the role of neutrophils on pathological cardiac remodeling has been pertained after acute myocardial infarction. However, whether neutrophils directly contribute to the pathogenesis of cardiac remodeling after events other than acute myocardial infarction remains unknown. Here we show that acute eccentric hypertrophy induced by aorto-caval fistula (ACF) in the rats induced an increase in the inflammatory response characterized by activation of the STAT pathway and increased infiltration of neutrophils in the myocardium. This early inflammation was associated with a decrease in interstitial collagen accumulation and an increase in myocyte apoptosis. Neutrophil infiltration blockade attenuated MMP activation, ECM degradation, and myocyte apoptosis induced by ACF at 24 hours and attenuated the development of eccentric hypertrophy induced by ACF at 2 and 3 weeks, suggesting a causal relationship between neutrophils and the ACF-induced cardiac remodeling. In contrast, sustained neutrophil depletion over 4 weeks resulted in adverse cardiac remodeling with further increase in cardiac dilatation and macrophage infiltration, but with no change in myocyte apoptosis level. These data support a functional role for neutrophils in MMP activation, ECM degradation, and myocyte apoptosis during eccentric cardiac hypertrophy and underscore the adverse effects of chronic anti-neutrophil therapy on cardiac remodeling induced by early volume overload.

Left ventricular remodeling with exercise in hypertension.

We investigated how exercise training superimposed on chronic hypertension impacted left ventricular remodeling. Cardiomyocyte hypertrophy, apoptosis, and proliferation in hearts from female spontaneously hypertensive rats (SHRs) were examined. Four-month-old SHR animals were placed into a sedentary group (SHR-SED; n = 18) or a treadmill running group (SHR-TRD, 20 m/min, 1 h/day, 5 days/wk, 12 wk; n = 18). Age-matched, sedentary Wistar Kyoto (WKY) rats were controls (n = 18). Heart weight was greater in SHR-TRD vs. both WKY (P < 0.01) and SHR-SED (P < 0.05). Morphometric-derived left ventricular anterior, posterior, and septal wall thickness were increased in SHR-SED relative to WKY and augmented in SHR-TRD. Cardiomyocyte surface area, length, and width were increased in SHR-SED relative to WKY and further increased in SHR-TRD. Calcineurin abundance was increased in SHR-SED vs. WKY (P < 0.001) and attenuated in SHR-TRD relative to SHR-SED (P < 0.05). Protein abundance and mRNA of Akt was not different among groups. The rate of apoptosis was increased in SHR-SED relative to WKY and mitigated in SHR-TRD. The abundance of Ki-67(+) cells across groups was not statistically different across groups. The abundance of cardiac progenitor cells (c-Kit(+) cells) was increased in SHR-TRD relative to WKY. These data suggest that exercise training superimposed on hypertension augmented cardiomyocyte hypertrophy, despite attenuating calcineurin abundance. Exercise training also mitigated apoptosis in hypertension and showed a tendency to enhance the abundance of cardiac progenitor cells, resulting in a more favorable cardiomyocyte number in the exercise-trained hypertensive heart.

Sympathetic activation causes focal adhesion signaling alteration in early compensated volume overload attributable to isolated mitral regurgitation in the dog.

We reported that left ventricular (LV) dilatation after 4 weeks of isolated mitral regurgitation (MR) in the dogs is marked by extracellular matrix loss and an increase in adrenergic drive. Given that extracellular matrix proteins and their receptor integrins influence beta-adrenergic receptor (beta-AR) responses in vitro, we tested whether beta1-AR activation modulates focal adhesion (FA) signaling and LV remodeling in these same dogs with isolated MR. Normal dogs were compared with dogs with MR of a 4-week duration and with MR dogs treated with beta(1)-AR blockade (beta(1)-RB) (extended-release metoprolol succinate, 100 mg QD) that was started 24 hours after MR induction. In MR LVs, a decrease in collagen accumulation compared with normal dogs was associated with a decrease in FA kinase tyrosine phosphorylation, along with FA kinase interaction with adapter and cytoskeletal proteins, p130(Cas) and paxillin, respectively, as determined by immunoprecipitation assays. There was increased phosphorylation of stress related molecules p38 mitogen-activated protein kinase (MAPK) and Hsp27 and survival signaling kinases extracellular signal-regulated kinase 1/2 and AKT, with no evidence of cardiomyocyte apoptosis. beta(1)-RB attenuated FA signaling loss and prevented p38 MAPK, Hsp27, and AKT phosphorylation induced by MR and significantly increased LV epicardial collagen content. However, beta(1)-RB did not improve LV endocardial collagen loss or LV dilatation induced by MR. Isolated myocytes from normal and MR dog hearts treated with beta(1)- or beta(2)-AR agonists demonstrated no difference in FA kinase, p38 MAPK, Hsp27, or AKT phosphorylation. These results showed that chronic stimulation of beta(1)-AR during early compensated MR impairs FA signaling that may affect myocyte/fibroblast-extracellular matrix scaffolding necessary for LV remodeling.