Publications by authors named "Mark J Aronovitz"
Article Synopsis
- The study investigates how the CRIB domain of mixed lineage kinase 3 (MLK3) affects blood pressure and heart function, particularly under conditions of pressure overload.
- Mice with mutations in the CRIB domain showed increased blood pressure and developed heart muscle thickening (hypertrophy), but normal baseline heart function, suggesting important roles for MLK3 in cardiovascular health.
- The research highlights that altering the CRIB domain in MLK3 leads to significant changes in blood pressure regulation and heart response to pressure overload, indicating its importance in maintaining heart function and cardiovascular stability.
Article Synopsis
- cGMP-dependent protein kinase 1α (PKG1α) supports heart function in response to pressure overload, but its activation often leads to hypotension, which limits its therapeutic use in heart failure.* -
- The study found that mixed lineage kinase 3 (MLK3) interacts with PKG1α and is crucial for maintaining left ventricle (LV) function without affecting blood pressure (BP), even in conditions of heart failure.* -
- Results indicate that enhancing MLK3 activity could help improve heart function in heart failure patients while preventing the drop in blood pressure typically associated with PKG1α activation.*
Article Synopsis
- Mineralocorticoid receptor (MR) antagonists have shown promise in reducing heart failure hospitalization and mortality, but the specific mechanisms behind this benefit, particularly involving smooth muscle cells (SMCs), have not been previously studied.
- In a mouse model, researchers deleted MR from SMCs and found that this deletion improved various heart failure indicators, including ejection fraction and exercise capacity, compared to MR-intact mice after induced heart failure.
- The study suggests that blocking MR in SMCs can enhance cardiac blood supply during heart pressure overload, which helps to reduce harmful cardiac remodeling associated with heart failure progression.
Background: Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies.
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- Sacubitril/valsartan (Sac/Val) is a treatment for heart failure that works by preventing the breakdown of natriuretic peptides, potentially enhancing cGMP-PKG signaling.
- Researchers studied the impact of Sac/Val on mice with a specific mutation affecting PKG to see if it was necessary for the drug's effectiveness.
- Despite the mutation, Sac/Val still improved heart structure and function in mice, indicating that other signaling pathways aside from the natriuretic peptide-cGMP-PKG pathway may also contribute to its benefits in heart failure.
Article Synopsis
- Transverse aortic constriction (TAC) is a mouse model used to study heart issues caused by increased pressure, and the severity of the constriction is determined by the size of the needle used during surgery.* -
- In a study, adult male mice underwent TAC surgery with different needle gauges (25G, 26G, 27G) to assess how varying levels of constriction affected heart health over four weeks compared to control mice.* -
- Results showed that tighter constriction (27G) led to more serious heart problems, including heart failure symptoms and kidney atrophy, while different constriction levels resulted in distinct cardiac responses, suggesting they could be useful in various research scenarios.*
Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload.
Am J Physiol Heart Circ Physiol
January 2019
Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH-terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study, we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF.
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- * A study using a special mouse model revealed that blocking a specific estrogen receptor pathway leads to significant weight gain and glucose intolerance.
- * The research showed that activating a protein called PP2A can improve metabolism issues linked to missing this estrogen signaling, highlighting its importance in metabolic balance during menopause.
Article Synopsis
- Heart failure is a critical health concern that involves the development of cardiac fibrosis, which can worsen heart function; TGF-β1 is a key player in promoting fibrosis but also has regulatory pathways, while BMP9, a TGF-β family member, may help mitigate this effect.
- Research indicates that BMP9 levels are elevated in heart failure patients and that it reduces collagen production in human cardiac fibroblasts, suggesting a protective role against fibrosis.
- In animal models, BMP9 treatment showed potential benefits in reducing cardiac fibrosis and improving heart function, while disruption of endoglin, which interacts with BMP9, further enhances BMP9's positive effect on the heart.
Introduction: Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFβ1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure.
Hypothesis: We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure.
Article Synopsis
- Activin like kinase-1 (AlK-1) is important for signaling in the TGFβ family and affects blood vessel growth; reduced activity is linked to abnormal blood vessel formations.
- A study using AlK-1 conditional knockout mice showed that removing AlK-1 led to worse heart health outcomes, like reduced survival rates and heart function deterioration.
- After 14 days, cKO-TAM mice (with AlK-1 deletion) had smaller body mass, increased heart and lung weight, and changes in heart pressure and contractility compared to control groups, but no signs of heart fibrosis were found.
Article Synopsis
- MicroRNA-offset RNAs (moRs), previously thought to be inactive by-products of microRNA (miR) production, are now shown to have biological effects.
- Research has revealed that moR-21 can significantly influence gene expression and inhibit the growth of vascular smooth muscle cells (VSMC).
- The study indicates that moR-21 and miR-21 may regulate different genes within the same pathway, sometimes opposing each other, and their function depends on Argonaute 2 (Ago2).
Background: Right ventricular (RV) failure is a major cause of mortality worldwide and is often a consequence of RV pressure overload (RVPO). Endoglin is a coreceptor for the profibrogenic cytokine, transforming growth factor beta 1 (TGF-β1). TGF-β1 signaling by the canonical transient receptor protein channel 6 (TRPC-6) was recently reported to stimulate calcineurin-mediated myofibroblast transformation, a critical component of cardiac fibrosis.
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- Decreased heart rate variability (HRV) is linked to higher risks of sudden death and cardiovascular issues, particularly in type 1 diabetes models like the Akita mouse.
- The study found that hyperactive glycogen synthase kinase-3β (GSK3β) in the Akita mouse heart leads to lowering the sterol response element-binding protein (SREBP-1) and disrupting parasympathetic heart rate control, as indicated by decreased levels of specific ion channels.
- Inhibiting GSK3β with substances like Kenpaullone and lithium showed potential to restore SREBP-1 and ion channel function, highlighting GSK3β as a promising target for treating heart issues related to diabetic autonom
Article Synopsis
- Right ventricular (RV) failure significantly contributes to mortality in lung disease and left heart failure; this study aimed to analyze biventricular hemodynamics and the expression of proteins involved in cardiac remodeling in mouse models of RV pressure overload (RVPO).
- Male mice were subjected to pulmonary artery or thoracic aorta constriction, and measurements were taken on RV and left ventricular function, as well as tissue analysis for changes in cardiac structure like hypertrophy and fibrosis.
- Results showed differing impacts of primary and secondary RVPO on biventricular function, with variations in stroke work, pressure dynamics, and cardiac remodeling proteins (calcineurin and TGFβ1), highlighting unique responses in heart structure and function between the two types
Rapid estrogen receptor signaling mediates estrogen-induced inhibition of vascular smooth muscle cell proliferation.
Arterioscler Thromb Vasc Biol
August 2013
Objective: The proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in vascular diseases, such as atherosclerosis and restenosis, after percutaneous coronary intervention. Many studies have shown that estrogen inhibits VSMC proliferation in response to vascular injury in the mouse carotid injury model. However, the mechanisms that mediate these effects remain unclear.
View Article and Find Full Text PDFEstrogen receptor-mediated regulation of microRNA inhibits proliferation of vascular smooth muscle cells.
Arterioscler Thromb Vasc Biol
February 2013
Objective: Estradiol (E2) regulates gene transcription by activating estrogen receptor-α and estrogen receptor-β. Many of the genes regulated by E2 via estrogen receptors are repressed, yet the molecular mechanisms that mediate E2-induced gene repression are currently unknown. We hypothesized that E2, acting through estrogen receptors, regulates expression of microRNAs (miRs) leading to repression of expression of specific target genes.
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- The study investigates the complex cardiovascular effects of estrogen, highlighting both its protective and harmful roles, with a focus on estrogen receptors (ERs) and their dual mechanism of action.
- Researchers created a transgenic mouse to block rapid ER signaling, revealing its critical role in regulating gene responses and maintaining estrogen's protective effects on blood vessels.
- The findings suggest that rapid, nonnuclear ER signaling is essential for estrogen’s benefits in vascular health and could be a target for new treatments in cardiovascular diseases.
Mineralocorticoid receptor antagonism inhibits vein graft remodeling in mice.
J Thorac Cardiovasc Surg
June 2013
Article Synopsis
- The study investigates the high failure rates of vein grafts due to adverse remodeling, focusing on the role of the mineralocorticoid receptor (MR) in this process.
- Researchers used various methods to analyze MR expression in human vein tissue and found that MR inhibition can reduce vein graft remodeling in a mouse model.
- The results suggest that using MR antagonists, like spironolactone, could be an effective novel therapy for preserving vein grafts by decreasing inflammation and thickening of the grafts.
Article Synopsis
- Heart failure is a significant global health issue, and the study focuses on the role of the cytokine TGFβ1 in promoting cardiac fibrosis, which worsens heart failure.
- Researchers found that endoglin expression is higher in the hearts of people with heart failure and that it is necessary for TGFβ1 signaling in heart cells; reducing endoglin allows for better heart function and survival in mice models.
- The study suggests that soluble endoglin can disrupt TGFβ1 signaling and collagen production, presenting a new potential treatment strategy for heart failure by targeting endoglin to lessen cardiac fibrosis.
Left ventricular remodeling, including the deposition of excess extracellular matrix, is key to the pathogenesis of heart failure. The stress-inducible transcriptional regulator p8 is increased in failing human hearts and is required both for agonist-stimulated cardiomyocyte hypertrophy and for cardiac fibroblasts matrix metalloprotease-9 (MMP9) induction. In the heart, upregulation of autophagy is an adaptive response to stress and plays a causative role in cardiomyopathies.
View Article and Find Full Text PDFElevated soluble fms-like tyrosine kinase-1 levels in acute coronary occlusion.
Arterioscler Thromb Vasc Biol
February 2011
Article Synopsis
- Elevated levels of the protein sFLT1 were found in patients with acute coronary occlusion (ACO), indicating it could be used for early detection of this condition compared to other biomarkers like troponin I and creatine kinase.
- In a study, sFLT1 levels were measured in patients with ACO and other cardiac conditions, showing significantly higher levels in ACO cases, reinforcing its potential as a diagnostic tool.
- The findings suggest that sFLT1 may serve as an early marker of endothelial hypoxia during ACO, with levels rising shortly after symptom onset in both human and mouse models.
Article Synopsis
- Autophagy is a protective process that helps cells recycle components, and its dysfunction is linked to diseases like cancer and heart conditions.
- The study reveals that the protein p8 regulates autophagy; specifically, reducing p8 levels enhances autophagy and affects cell survival, particularly in heart cells.
- P8 represses the activity of a transcription factor called FoxO3, which promotes autophagy; when p8 is knocked down, FoxO3 interacts more with genes that increase autophagy, leading to changes in heart structure and function in mice lacking p8.
Article Synopsis
- Diabetic autonomic neuropathy (DAN) impairs cardiac parasympathetic responsiveness, partly due to reduced activation of the GIRK1 and GIRK4 K+ channels, which are crucial for heart function.
- The study identifies a mechanism where the lipid-sensitive transcription factor SREBP-1 regulates insulin's effect on this parasympathetic response in a mouse model of diabetes.
- Results show that insulin increases the expression of GIRK1 and SREBP-1, enhancing cardiac response, while deficiencies in these pathways contribute to the complications associated with DAN.