Rakesh C Kukreja

Virginia Commonwealth University | VCU · Division of Cardiology

Robust activation of mTOR (mammalian target of rapamycin) signaling in diabetes exacerbates myocardial injury following lethal ischemia due to accelerated cardiomyocyte death with cardiac remodeling and inflammatory responses. We examined the effect of rapamycin (RAPA, mTOR inhibitor) on cardiac remodeling and inflammation following myocardial isch...

Phosphodiesterase 5 (PDE5) is an enzyme that catalyzes the degradation of cGMP to its inactive form, 5′-GMP. The inhibition of PDE5 leads to the increase in bioavailability of cGMP which exerts its downstream signaling effects through the activation of protein kinase G (PKG). The dysregulation of cGMP-PKG signaling cascade plays a critical role in...

Androgen deprivation therapy (ADT) is the primary systemic therapy for treating advanced or metastatic prostate cancer (PCa) and has improved survival outcomes in patients with PCa. However, ADT may develop metabolic and cardiovascular adverse events that impact the quality of life and lifespan in PCa survivors. The present study was designed to es...

Backgound: Chemoimmunotherapy with Doxorubicin (DOX) and Trastuzumab (Trast, a monoclonal antibody against human epidermal growth factor receptor 2, ERBB2) has synergistic effects with immense improvement in disease-free survival in breast cancer patients. However, because of the high incidence of heart failure, the concomitant treatment with DOX a...

Cyclic guanosine monophosphate (cGMP), an important intracellular second messenger, mediates cellular functional responses in all vital organs. Phosphodiesterase 5 (PDE5) is one of the 11 members of the cyclic nucleotide phosphodiesterase (PDE) family that specifically targets cGMP generated by nitric oxide–driven activation of the soluble guanylyl...

Mucin MUC4 is an aberrantly expressed oncogene in pancreatic ductal adenocarcinoma (PDAC), yet no pharmacological inhibitors have been identified to target MUC4. Here, we adapted an in silico screening method using the Cancer Therapeutic Response Database (CTRD) to Identify Small Molecule Inhibitors against Mucins (SMIMs). We found that Bosutinib a...

Type 2 diabetes (T2D) is one of the major risk factors for developing cardiovascular disease and the resultant devastating morbidity and mortality. The key features of T2D are hyperglycemia, hyperlipidemia, insulin resistance, and impaired insulin secretion. Patients with diabetes and myocardial infarction have worse prognosis than those without T2...

Background: Triple Negative Breast Cancer (TNBC) is an aggressive form of cancer and accounts for 10-20 % of all breast cancer types. TNBC patients are widely treated with chemotherapeutic drugs such as doxorubicin (Dox), which is a primary standard of care. Dox treatment results in unwanted side effects including cardiac dysfunction and skeletal...

We developed a preclinical model of myocardial ischemia/reperfusion (I/R) injury in conscious diabetic rabbits to identify an early pharmacological intervention for patients with diabetes and acute myocardial infarction (AMI). Here, we describe a reproducible protocol for induction of diabetes with subsequent manifestation of myocardial I/R injury...

Acid ceramidase (murine gene code: Asah1) (50 kDa) belongs to N‐terminal nucleophile hydrolase family. This enzyme is located in the lysosome, which mediates conversion of ceramide (CER) into sphingosine and free fatty acids at acidic pH. CER plays an important role in intracellular sphingolipid metabolism and its increase causes inflammation. The...

Cyclic nucleotide phosphodiesterases (PDEs) are superfamily of enzymes that regulate the spatial and temporal relationship of second messenger signaling in the cellular system. Among the 11 different families of PDEs, phosphodiesterase 1 (PDE1) sub-family of enzymes hydrolyze both 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosi...

Persistent activation of mTOR (mammalian target of rapamycin) in diabetes increases the vulnerability of the heart to ischemia/reperfusion (I/R) injury. We show here that infusion of rapamycin (mTOR inhibitor) at reperfusion following ischemia reduced myocardial infarct size and apoptosis with restoration of cardiac function in type 1 diabetic rabb...

Background: Doxorubicin (DOX) is a chemotherapeutic agent for multiple cancers, however, it causes systemic inflammation with multi-organ injury, including irreversible skeletal muscle (SM) dysfunction and cardiotoxicity. Treatment either with phosphodiesterase 5 inhibitor, sildenafil (SILD) or mammalian target of rapamycin (mTOR) inhibitor, Rapamy...

Purpose: Docetaxel plays an indispensable role in the management of advanced prostate cancer (PCa). However, more than half of patients do not respond to docetaxel, and those good responders frequently experience significant cumulative toxicity, which limits its dose duration and intensity. Hence, a second agent that could increase the initial eff...

Abusive chronic alcohol consumption can cause metabolic and functional derangements in the heart and is a risk factor for development of non-ischemic cardiomyopathy. microRNA 214 (miR-214) is a molecular sensor of stress signals that negatively impacts cell survival. Considering cardioprotective and microRNA modulatory effects of sildenafil, a phos...

Androgen deprivation therapy (ADT) is the primary systemic therapy for treating locally advanced or metastatic prostate cancer (PCa). Despite its positive effect on PCa patient survival, ADT causes various adverse effects, including increased cardiovascular risk factors and cardiotoxicity. Lifespans extension, early use of ADT, and second-line trea...

Patients with metabolic syndrome (MetS) often exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide (NO) production and/or bioavailability. Since phosphodiesterase 5 (PDE5) inhibitors restore NO signaling, we hypothesized that chronic treatment with long-acting PDE5 inhibitor tadalafil may enhance plasma NO levels and...

Increased secretion of exosomes from arterial smooth muscle cells (SMCs) has been shown to contribute to arterial medial calcification (AMC) associated with accumulation of calcium deposits in the arterial wall and osteoblastic differentiation of SMCs. In this study, we further explored the molecular mechanisms increasing exosome secretion during A...

Doxorubicin (Dox) is an effective chemotherapeutic agent which is widely used clinically to treat solid tumors. Unfortunately, the use of Dox has been restricted due to serious side effects including skeletal muscle toxicity. The current dogma is that Dox‐induced muscle toxicity (DIMT) is mediated through enhanced oxidative stress, inflammation, an...

Arterial medial calcification (AMC) involves an increased small extracellular vesicle (sEV) secretion and apatite calcium precipitation in the arterial wall. The mechanisms mediating AMC remain poorly understood. In the present study, smooth muscle-specific acid ceramidase (Ac) gene knockout mice (Asah1fl/fl/SMCre) were used to demonstrate the role...

Background: Multi-drug resistance (MDR) develops because cancer cells evade toxicity of several structurally unrelated drugs. Besides other mechanisms, MDR is linked to the overexpression of ATP Binding Cassette (ABC), transporters, among which ABCB1 is the best characterized one. Since overactivation of PI3K/Akt/mTOR plays a pivotal role in the g...

Aims: Deregulation of mTOR (mammalian target of rapamycin) signaling occurs in diabetes, which exacerbates injury following myocardial infarction. We therefore investigated the infarct-limiting effect of chronic treatment with rapamycin (RAPA, mTOR inhibitor) in diabetic mice following myocardial ischemia/reperfusion (I/R) injury and delineated th...

Background: Dysregulation of miRNAs is associated with the pathogenesis of cardiovascular diseases. miR-17-92 cluster has been identified as a negative regulator of inflammation in rheumatoid arthritis. In diabetes, the persistent activation of NLRP3 inflammasome contributes to cardiac dysfunction and the severity of I/R. NLRP3 inflammasome consist...

Background Doxorubicin (DOX) is a widely used and effective chemotherapeutic agent, but is associated with a delayed and progressive cardiomyopathy. Phosphodiesterase 5 (PDE5) inhibitors have been shown to be protective of heart function with DOX co‐treatment in animal models, but PDE5 is expressed at low levels in human heart. In contrast, phospho...

Doxorubicin (DOX) is the most effective anti‐tumor agent to treat wide variety of solid tumors, including the breast cancer. However, it is not known whether combination treatment of embryonic stem cells derived exosomes (ES‐exos) with DOX influences the killing of breast cancer cells. To address this question, breast cancer cell lines, MDA‐MB231 a...

The mammalian target of rapamycin complex 1 (mTORC1) signaling on late endosomes (LE)/lysosomes may control cargo selection, membrane biogenesis, exosome secretion and lysosome trafficking, which is fine controlled by lysosomal sphingolipids such as ceramide. This lysosomal sphingolipid‐regulated mTOR signaling may be a crucial molecular mechanism...

Background Doxorubicin chemotherapy is used across a range of adult and pediatric malignancies. Cardiac toxicity is common, and dysfunction develops over time in many patients. Biomarkers used for predicting late cardiac dysfunction following doxorubicin exposure have shown promise. Preclinical studies have demonstrated potential cardioprotective e...

Mechanistic/mammalian target of rapamycin (mTOR), an atypical serine/threonine kinase of the phosphoinositide 3-kinase- (PI3K-) related kinase family, elicits a vital role in diverse cellular processes, including cellular growth, proliferation, survival, protein synthesis, autophagy, and metabolism. In the cardiovascular system, the mTOR signaling...

Radiation of the chest during cancer therapy is deleterious to the heart, mostly due to oxidative stress and inflammation related injury. A single sub-lethal dose of irradiation has been shown to result in compensatory up-regulation of the myocardial connexin-43 (Cx43), activation of the protein kinase C (PKC) signaling along with the decline of mi...

Aim Potassium channel accessory subunits (Kvβ) play a key role in cardiac electrical activity through ion channel modulation. In the present study we hypothesize that Kvβ2 regulates skeletal muscle growth and fiber phenotype via protein‐protein interactions. Methods Kvβ2 knockout mouse model was used for morphometric, immunohistochemical and bioch...

Background Several studies have demonstrated cardioprotective effects of the phosphodiesterase 5 inhibitor, sildenafil (SILD), in the setting of myocardial ischemia and reperfusion (MI/R) in mice and rabbits. However, it is unclear whether sildenafil exerts postconditioning effect in normal and diabetic rabbits. Methods and Results To induce diabe...

Background Myocardial ischemia reperfusion (I/R) injury associated with cardiovascular risk factors and comorbidities, including Diabetes (DM), is a major complication for development of heart failure. Mammalian target of Rapamycin (mTOR) is robustly active in DM and further exacerbated during I/R. mTOR inhibition with rapamycin at reperfusion pres...

We previously demonstrated the role of Kvβ1.1 subunit of voltage-activated potassium channel in heart for its sensory roles in detecting changes in NADH/NAD and modulation of ion channel. However, the pharmacological role for the association of Kvβ1 via its binding to ligands such as cortisone and its analogs remains unknown. Therefore, we investig...

Background: Enhanced mammalian target of rapamycin (mTOR) signaling contributes to the pathogenesis of diabetes and plays a critical role in myocardial ischemia/reperfusion (I/R) injury. Rapatar is a novel nanoformulated micellar of rapamycin, a putative inhibitor of mTOR, that have been rationally designed to increase water solubility of rapamyci...

Doxorubicin (Dox) is an effective anticancer drug. Unfortunately, it causes cardiac and muscle toxicity due to increased oxidative stress and inflammation; however, it remains unknown whether Dox induces “pyroptosis” — an inflammation-mediated cell death. We investigated whether Dox induces pyroptosis in mouse soleus muscle (Sol 8) cells in vitro a...

Irradiation of normal tissues leads to acute increase in reactive oxygen/nitrogen species that serve as intra- and inter-cellular signaling to alter cell and tissue function. In the case of chest irradiation, it can affect the heart, blood vessels, and lungs, with consequent tissue remodelation and adverse side effects and symptoms. This complex pr...

Prompt coronary reperfusion is the gold standard for minimizing injury following acute myocardial infarction. Rapamycin, mammalian target of Rapamycin (mTOR) inhibitor, exerts preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. We hypothesized that Rapamycin, given at the onset of reperfusion, reduces myocardial...

The chemotherapeutic use of doxorubicin (Dox) is hindered due to the development of irreversible cardiotoxicity. Specifically, childhood cancer survivors are at greater risk of Dox-induced cardiovascular complications. Because of the potent cardioprotective effect of phosphodiesterase 5 (PDE5) inhibitors, we examined the effect of long-acting PDE5...

This is an editorial focus.

Diabetes is associated with high risk of ischemic heart disease. We previously showed that phosphodiesterase 5 inhibitor - tadalafil (TAD) induces cardioprotection against ischemia/ reperfusion (I/R) injury in diabetic mice. Hydroxychloroquine (HCQ) is a widely used antimalarial and anti-inflammatory drug, which was reported to reduce hyperglycemia...

Myocardial infarction (MI) is a major cardiovascular disease (CVD) and ranks among the leading causes of morbidity and mortality in humans, worldwide. Despite advances in disease prevention and treatment strategies, majority of the developed and developing world's suffer higher disease burden from MI, and incur billions of dollars in healthcare cos...

Mammalian target of rapamycin (mTOR) signaling plays a crucial role in metabolic stress, aging, and cardiovascular disease through the maintenance of intracellular energy metabolism, nutrient availability, and cellular growth. mTOR exists in two functionally distinct complexes referred to as mTOR complex 1 (mTORC1) and mTORC2. In recent years, ther...

Doxorubicin (DOX, Adriamycin) is a broad-spectrum chemotherapeutic drug used to treat a variety of cancers, although its clinical use is restricted by irreversible cardiotoxicity. Earlier studies show that beet root juice (BRJ), a natural and safe herbal product with high levels of nitrate and antioxidants, is a potent chemopreventive agent; howeve...

The aim of this study was to measure expression levels of microRNAs (miRNAs) (miRNA-1, -15b and -21) in the rat myocardium after a single dose of ionizing radiation (6-7 Gy/min, total 25 Gy). The rats were treated with selected drugs (Atorvastatin, acetylsalicylic acid (ASA), Tadalafil, Enbrel) for six weeks after irradiation. MiRNAs levels were me...

Intercellular connexin-43 (Cx43) channels are essential for electrical coupling and direct cardiac cell to cell communication to ensure heart function. Expression of Cx43 is altered due to stressful conditions and also affected by the alterations in extracellular matrix. We aimed to explore the effect of chest irradiation on myocardial expression o...

Despite their recognized cardiotoxic effects, anthracyclines remain an essential component in many anticancer regimens due to their superior antitumor efficacy. Epidemiologic data revealed that about one-third of cancer patients have hypertension, which is the most common comorbidity in cancer registries. The purpose of this review is to assess whe...

We previously reported that Sildenafil enhances apoptosis and antitumor efficacy of doxorubicin (DOX) while attenuating its cardiotoxic effect in prostate cancer. In the present study, we investigated the mechanism by which sildenafil sensitizes DOX in killing of prostate cancer (PCa) cells, DU145. The death receptor Fas (APO-1 or CD95) induces apo...

Background: The selective inhibitor of mammalian target of rapamycin (mTOR), rapamycin (RAPA), has been shown to exert preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. Two distinct mTOR complexes (mTORC1 and mTORC2) differentially regulate cardiomyocyte apoptosis and tissue damage following myocardial infarct...

Background: Hydroxychloroquine (HCQ) is an antimalarial drug, which is also widely used to treat chronic rheumatologic diseases. Since HCQ was reported to inhibit cell autophagy and to activate extracellular-signal-regulated kinase 5 (ERK5) in vascular endothelial cells, we designed the current study to determine the effects of HCQ on cardiac ische...

Background: Persistent activation of the mammalian target of rapamycin (mTOR) is implicated in diabetic complications and plays a critical role in myocardial injury following ischemia/reperfusion. Recently we reported that mTOR inhibition with rapamycin improves cardiac function in type 2 diabetic (T2D) mice through attenuation of oxidative stress...

Cyclic GMP-dependent protein kinase (PKG) is a serine-threonine kinase that mediates the cardioprotective effect of ischemic and pharmacologic preconditioning. Since hydrogen sulfide (H2S) has been implicated in mediating the cardioprotective effects of the cGMP modulators tadalafil and cinaciguat, we tested the hypothesis that myocardial gene ther...

Pancreatic cancer has the lowest five-year survival rate of all major cancers despite decades of effort to design and implement novel, more effective treatment options. In this study, we tested whether the dual PI3K/mTOR inhibitor BEZ235 (BEZ) potentiates the anti-tumor effects of doxorubicin (DOX) against pancreatic cancer. Co-treatment of BEZ235...

Diabetic patients suffer augmented severity of myocardial infarction. Excessive activation of the mammalian target of rapamycin (mTOR) and decreased activation of STAT3 are implicated in diabetic complications. Considering the potent cardioprotective effect of mTOR inhibitor, rapamycin, we hypothesized that reperfusion therapy with rapamycin would...

Ischemic heart disease is the leading cause of death for both men and women worldwide, accruing 7.4 million deaths in 2012. There has been a continued search for better cardioprotective modalities that would reduce myocardial ischemia-reperfusion injury. Among these attempts, a more convenient model of ischemic preconditioning, known as remote isch...

Objective Excessive intake of alcohol under diabetic condition leads to increased stress and causes both transient and lasting structural changes including fibrosis in heart. We tested the hypothesis whether phosphodiesterase5 (PDE5) inhibitor, sildenafil prevents alcohol‐induced cardiac dysfunction in Type 2 Diabetic (T2D) db/db mice and the role...

Objective Fatty Acid Ethyl Esters (FAEE) are esterified products of alcohol that can cause severe damage to tissue organs and are mediators of ethanol‐induced cytotoxic effects. The mechanism that underlie the onset, progression and severity of alcohol toxicity are poorly understood. Carboxylesterase3 (CES3) is an enzyme responsible for esterificat...

Transmyocardial Laser Revascularization (TMR) is an approved treatment of end stage coronary artery disease. Explanation on how TMR improves symptoms is currently unknown although myocardial angiogenesis and denervation are considered as possible mechanisms. In this study, we investigated the potential preconditioning effect of TMR in a model of my...

Rationale: Despite 4 decades of intense effort and substantial financial investment, the cardioprotection field has failed to deliver a single drug that effectively reduces myocardial infarct size in patients. A major reason is insufficient rigor and reproducibility in preclinical studies. Objective: To develop a multicenter, randomized, control...

Background: Cardiotoxicity is a major clinical limitation with doxorubicin (DOX). Also, the PI3K/Akt survival pathway is one of the most commonly mutated pathways in cancer. Therefore, the combination of kinase inhibitors and chemotherapy, such as DOX, are necessary for achieving cancer control. The PI3K pathway is also critical for protecting the...

Background: Diabetic patients suffer augmented severity of myocardial infarction. Excessive activation of the mammalian target of rapamycin (mTOR) is implicated in diabetic complications and plays a critical role in myocardial reperfusion injury following ischemia. mTOR inhibition with rapamycin improves cardiac function in type 2 diabetic (T2D) he...

The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect...

Ingestion of high dietary nitrate in the form of beetroot juice (BRJ) has been shown to exert antihypertensive effects in humans through increasing cyclic guanosine monophosphate (cGMP) levels. Since enhanced cGMP protects against myocardial ischemia-reperfusion (I/R) injury through upregulation of hydrogen sulfide (H2S), we tested the hypothesis t...

Ataxia‐telangiectasia mutated (ATM) kinase, the mutation of which causes the autosomal recessive disease ataxia‐telangiectasia, plays an essential role in the maintenance of genome stability (reviewed in ref. [1][1]). ATM (a serine/threonine protein kinase) senses DNA double‐strand breaks and

Purpose Phosphodiesterase-5 (PDE5) inhibitors were shown to exert powerful protection in various animal models of cardiomyopathy. Tadalafil is a long-acting and highly specific PDE5 inhibitor, which makes it the most attractive in its class for long-term management of patients with heart failure. We studied the effects of tadalafil in attenuating...

Objectives: Myocardial synchronization and proper heart function depends on the expression and subcellular distribution of intercellular connexin-43 (Cx43) channels that are essential for electrical coupling and direct cell-to-cell communication. Radiotherapy is applied to treat cancer but chest irradiation can induce heart disease. We hypothesized...

One of the most widely used methods of treating oncological patients is ionizing radiation therapy. Radiation beam causes damage to the cancer cells which can reduce cancerous mass and leads to recovery of the oncological patients. On the other hand irradiation of other nearby tissues like myocardium can cause some damage which can induce serious h...

Despite modern radiotherapy techniques, treatment of oncological patients in some cases inevitably involves irradiation of normal tissues causing undesired side effects. Exposure of oncological patients to therapeutic doses of chest irradiation has been significant source of cardiovascular morbidity and mortality. The cellular response to radiation...

-Maintaining physiological levels of hydrogen sulfide (H2S) during ischemia is necessary to limit injury to the heart. Due to the anti-inflammatory effects of H2S, we proposed that the H2S donor, Na2S, would attenuate myocardial injury through upregulation of 'protective' microRNA (miR)-21 and suppression of the inflammasome, a macromolecular struc...