Gene transfer for ischemic heart failure in a preclinical model.

Various emerging technologies are being developed for patients with heart failure. Well-established preclinical evaluations are necessary to determine their efficacy and safety. Gene therapy using viral vectors is one of the most promising approaches for treating cardiac diseases.

Targeted gene therapy for the treatment of heart failure.

Chronic heart failure is one of the leading causes of morbidity and mortality in Western countries and is a major financial burden to the health care system. Pharmacologic treatment and implanting devices are the predominant therapeutic approaches. They improve survival and have offered significant improvement in patient quality of life, but they fall short of producing an authentic remedy.

Development of a preclinical model of ischemic cardiomyopathy in swine.

A number of promising therapies for ischemic cardiomyopathy are emerging, and the role of translational research in testing the efficacy and safety of these agents in relevant clinical models has become important. The goal of this study was to develop a chronic model of ischemic cardiomyopathy in a large animal model. In this study, 40 consecutive pigs were initially enrolled.

Long-term in vivo resistin overexpression induces myocardial dysfunction and remodeling in rats.

We have previously reported that resistin induces hypertrophy and impairs contractility in isolated rat cardiomyocytes. To examine the long-term cardiovascular effects of resistin, we induced in vivo overexpression of resistin using adeno-associated virus serotype 9 injected by tail vein in rats and compared to control animals. Ten weeks after viral injection, overexpression of resistin was associated with increased ratio of left ventricular (LV) weight/body weight, increased end-systolic LV volume and significant decrease in LV contractility, measured by the end-systolic pressure volume relationship slope in LV pressure volume loops, compared to controls.

Assessment of cardiovascular fibrosis using novel fluorescent probes.

Cardiovascular fibrosis resulted from pressure overload or ischemia could alter myocardial stiffness and lead to ventricular dysfunction. Fluorescently labeled collagen-binding protein CNA 35, derived from the surface component of Staphylococcus aureus, and a novel synthetic biphenylalanine containing peptide are applied to stain fibrosis associated collagen and myocytes, respectively. Detailed pathological characteristics of cardiovascular fibrosis could be identified clearly in 2 hours.

A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes.

As a master transcription factor in cellular responses to external stress, tumor suppressor p53 is tightly regulated. Excessive p53 activity during myocardial ischemia causes irreversible cellular injury and cardiomyocyte death. p53 activation is dependent on lysine acetylation by the lysine acetyltransferase and transcriptional coactivator CREB-binding protein (CBP) and on acetylation-directed CBP recruitment for p53 target gene expression.

Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways.

Resistin has been suggested to be involved in the development of diabetes and insulin resistance. We recently reported that resistin is expressed in diabetic hearts and promotes cardiac hypertrophy; however, the mechanisms underlying this process are currently unknown. Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance.

Cyclosporine attenuates cardiomyocyte hypertrophy induced by RAF1 mutants in Noonan and LEOPARD syndromes.

RAS activation is implicated in physiologic and pathologic cardiac hypertrophy. Cross-talk between the Ras and calcineurin pathways, the latter also having been implicated in cardiac hypertrophy, has been suspected for pathologic hypertrophy. Our recent discovery that germ-line mutations in RAF1, which encodes a downstream RAS effector, cause Noonan and LEOPARD syndromes with a high prevalence of hypertrophic cardiomyopathy provided an opportunity to elaborate the role of RAF1 in cardiomyocyte biology.

SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure.

Background: Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy improves mechanical function in heart failure and is under evaluation in a clinical trial. A critical question is whether SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum calcium (SR Ca(2+)) leak, cellular triggered activity, and ventricular arrhythmias in the failing heart.

Methods And Results: We studied the influence of SERCA2a gene therapy on ventricular arrhythmogenesis in a rat chronic heart failure model.

Rescuing the failing heart by targeted gene transfer.

Congestive heart failure is a major cause of morbidity and mortality in the United States. Although progress in conventional treatments is making steady and incremental gains to decrease heart failure mortality, there is a critical need to explore new therapeutic approaches. Gene therapy was initially applied in the clinical setting for inherited monogenic disorders.

Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle.

Muscular dystrophies (MDs) comprise a group of degenerative muscle disorders characterized by progressive muscle wasting and often premature death. The primary defect common to most MDs involves disruption of the dystrophin-glycoprotein complex (DGC). This leads to sarcolemmal instability and Ca(2+) influx, inducing cellular necrosis.

SERCA2a controls the mode of agonist-induced intracellular Ca2+ signal, transcription factor NFAT and proliferation in human vascular smooth muscle cells.

In blood vessels, tone is maintained by agonist-induced cytosolic Ca(2+) oscillations of quiescent/contractile vascular smooth muscle cells (VSMCs). However, in synthetic/proliferative VSMCs, Gq/phosphoinositide receptor-coupled agonists trigger a steady-state increase in cytosolic Ca(2+) followed by a Store Operated Calcium Entry (SOCE) which translates into activation of the proliferation-associated transcription factor NFAT. Here, we report that in human coronary artery smooth muscle cells (hCASMCs), the sarco/endoplasmic reticulum calcium ATPase type 2a (SERCA2a) expressed in the contractile form of the hCASMCs, controls the nature of the agonist-induced Ca(2+) transient and the resulting down-stream signaling pathway.

Method of gene delivery in large animal models of cardiovascular diseases.

Cardiovascular disease is a major cause of morbidity and mortality in contemporary societies. While progress in conventional treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore new and potentially therapeutic approaches. Gene therapy, which was initially envisioned as a treatment strategy for inherited monogenic disorders, has been found to hold broader potential that also includes acquired polygenic diseases, such as atherosclerosis, arrhythmias, and heart failure.

Refilling Intracellular Calcium Stores.

Within the cardiac cell, the movements of calcium ions are tightly regulated by a number of regulatory proteins including pumps, and channels. The sarcoplasmic reticulum (SR) is in large part responsible for orchestrating these movements for the normal functioning of the cardiomyocyte. Alterations of SR regulatory proteins in failing hearts leads to abnormal Ca(2+) homeostasis and consequently to a deficient contractile state.

Adeno-associated virus serotype 8 ApoA-I gene transfer reduces progression of atherosclerosis in ApoE-KO mice: comparison of intramuscular and intravenous administration.

Apolipoprotein A-I (ApoA-I)/high-density lipoprotein (HDL)-raising treatments are effective antiatherosclerotic strategies. We have compared the antiatherogenic effects of human ApoA-I (hApoA-I) overexpression by intraportal and intramuscular gene transfer in atherosclerotic ApoE-knockout mice. Atherosclerotic lesions were induced by atherogenic diet.

Cardiac gene therapy with SERCA2a: from bench to bedside.

While progress in conventional treatments is making steady and incremental gains to reduce mortality associated with heart failure, there remains a need to explore potentially new therapeutic approaches. Heart failure induced by different etiologies such as coronary artery disease, hypertension, diabetes, infection, or inflammation results generally in calcium cycling dysregulation at the myocyte level. Recent advances in understanding of the molecular basis of these calcium cycling abnormalities, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within reach of gene-based therapy.

Cardiac gene therapy.

Heart failure is a chronic progressive disorder in which frequent and recurrent hospitalizations are associated with high mortality and morbidity. The incidence and the prevalence of this disease will increase with the increase in the number of the aging population of the United States. Understanding the molecular pathology and pathophysiology of this disease will uncover novel targets and therapies that can restore the function or attenuate the damage of malfunctioning cardiomyocytes by gene therapy that becomes an interesting and a promising field for the treatment of heart failure as well as other diseases in the future.

Gene therapy for heart failure.

Despite the progress achieved in conventional treatment modalities, heart failure remains a major cause of mortality and morbidity. The identification of novel signaling pathways has provided a solid scientific rationale which has stimulated preclinical development of gene-based therapies for heart failure. Advances in somatic gene transfer technologies have been crucial to the advent of the first human clinical trials which are currently in progress.

Multimodality imaging of chronic ischemia.

Although ischemic cardiomyopathy is commonly caused by chronic obstructive coronary disease, the mechanism of the cause is still under investigation. We present echocardiographic strain, magnetic resonance, and histology findings in a chronic ischemia model in preclinical study. This case illustrates the features of multimodality imaging in chronic obstructive coronary disease and gives us great insight into understanding the mechanism of ischemic cardiomyopathy.

Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant genetic disorder linked to numerous mutations in the sarcomeric proteins. The clinical presentation of FHC is highly variable, but it is a major cause of sudden cardiac death in young adults with no specific treatments. We tested the hypothesis that early intervention in Ca(2+) regulation may prevent pathological hypertrophy and improve cardiac function in a FHC displaying increased myofilament sensitivity to Ca(2+) and diastolic dysfunction.

β2-Adrenergic receptor signaling in the cardiac myocyte is modulated by interactions with CXCR4.

Chemokines are small secreted proteins with chemoattractant properties that play a key role in inflammation, metastasis, and embryonic development. We previously demonstrated a nonchemotactic role for one such chemokine pair, stromal cell-derived factor-1α and its G-protein coupled receptor, CXCR4. Stromal cell-derived factor-1/CXCR4 are expressed on cardiac myocytes and have direct consequences on cardiac myocyte physiology by inhibiting contractility in response to the nonselective β-adrenergic receptor (βAR) agonist, isoproterenol.

Amniotic fluid cells are more efficiently reprogrammed to pluripotency than adult cells.

Recently, cultured human adult skin cells were reprogrammed to induced pluripotent stem (iPS) cells, which have characteristics similar to human embryonic stem (hES) cells. Patient-derived iPS cells offer genetic and immunologic advantages for cell and tissue replacement or engineering. The efficiency of generating human iPS cells has been very low; therefore an easily and efficiently reprogrammed cell type is highly desired.

Gene delivery of sarcoplasmic reticulum calcium ATPase inhibits ventricular remodeling in ischemic mitral regurgitation.

Background: Mitral regurgitation (MR) doubles mortality after myocardial infarction (MI). We have demonstrated that MR worsens remodeling after MI and that early correction reverses remodeling. Sarcoplasmic reticulum Ca(+2)-ATPase (SERCA2a) is downregulated in this process.

Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis.

Cardiac apoptosis has been considered an important contributing factor to heart failure. Several subcellular mechanisms, including increased protein phosphatase 1 activity, have been suggested to induce apoptosis. Protein phosphatase 1 is regulated by an endogenous inhibitor-1 (I-1) that is activated upon phosphorylation at threonine 35 via protein kinase A.