A Non-natural Peptide Targeting the A-kinase Anchoring Function of PI3Kγ for Therapeutic cAMP Modulation in Pulmonary Cells.

A-kinase anchoring proteins (AKAPs) are key orchestrators of cyclic AMP (cAMP) signaling that act by recruiting protein kinase A (PKA) in proximity of its substrates and regulators to specific subcellular compartments. Modulation of AKAPs function offers the opportunity to achieve compartment-restricted modulation of the cAMP/PKA axis, paving the way to new targeted treatments. For instance, blocking the AKAP activity of PI3Kγ improves lung function by inducing cAMP-mediated bronchorelaxation, ion transport and anti-inflammatory responses. Here, we report the generation of a non-natural peptide, DRI-Pep #20, optimized to disrupt the AKAP function of PI3Kγ. DRI-Pep #20 mimicked the native interaction between the N-terminal domain of PI3Kγ and PKA, demonstrating nanomolar affinity for PKA, high resistance to protease degradation and high permeability to the pulmonary mucus barrier. DRI-Pep #20 triggered cAMP elevation both in vivo in the airway tract of mice upon intratracheal administration, and in vitro in bronchial epithelial cells of cystic fibrosis (CF) patients. In CF cells, DRI-Pep #20 rescued the defective function of the cAMP-operated channel cystic fibrosis conductance regulator (CFTR), by boosting the efficacy of approved CFTR modulators. Overall, this study unveils DRI-Pep #20 as a potent PI3Kγ/PKA disruptor for achieving therapeutic cAMP elevation in chronic respiratory disorders.

Preventing and Treating Anthracycline Cardiotoxicity: New Insights.

Anthracyclines are the cornerstone of many chemotherapy regimens for a variety of cancers. Unfortunately, their use is limited by a cumulative dose-dependent cardiotoxicity. Despite more than five decades of research, the biological mechanisms underlying anthracycline cardiotoxicity are not completely understood. In this review, we discuss the incidence, risk factors, types, and pathophysiology of anthracycline cardiotoxicity, as well as methods to prevent and treat this condition. We also summarize and discuss advances made in the last decade in the comprehension of the molecular mechanisms underlying the pathology.

MST1 mediates doxorubicin-induced cardiomyopathy by SIRT3 downregulation.

Heart failure is a major side effect of doxorubicin (DOX) treatment in patients with cancer. However, the mechanisms underlying the development of DOX-induced heart failure need to be addressed. This study aims to test whether the serine/threonine kinase MST1, a major Hippo pathway component, contributes to the development of DOX-induced myocardial injury. C57BL/6J WT mice and mice with cardiomyocyte-specific dominant-negative MST1 (kinase-dead) overexpression received three weekly injections of DOX, reaching a final cumulative dose of 18 mg/kg. Echocardiographic, histological and biochemical analyses were performed six weeks after the first DOX administration. The effects of MST1 inhibition on DOX-induced cardiomyocyte injury were also tested in vitro. MST1 signaling was significantly activated in cardiomyocytes in response to DOX treatment in vitro and in vivo. Wild-type (WT) mice treated with DOX developed cardiac dysfunction and mitochondrial abnormalities. However, these detrimental effects were abolished in mice with cardiomyocyte-specific overexpression of dominant-negative MST1 (DN-MST1) or treated with XMU-MP-1, a specific MST1 inhibitor, indicating that MST1 inhibition attenuates DOX-induced cardiac dysfunction. DOX treatment led to a significant downregulation of cardiac levels of SIRT3, a deacetylase involved in mitochondrial protection, in WT mice, which was rescued by MST1 inhibition. Pharmacological inhibition of SIRT3 blunted the protective effects of MST1 inhibition, indicating that SIRT3 downregulation mediates the cytotoxic effects of MST1 activation in response to DOX treatment. Finally, we found a significant upregulation of MST1 and downregulation of SIRT3 levels in human myocardial tissue of cancer patients treated with DOX. In summary, MST1 contributes to DOX-induced cardiomyopathy through SIRT3 downregulation.

Duality of Nrf2 in iron-overload cardiomyopathy.

Cardiomyopathy deeply affects quality of life and mortality of patients with b-thalassemia or with transfusion-dependent myelodysplastic syndromes. Recently, a link between Nrf2 activity and iron metabolism has been reported in liver ironoverload murine models. Here, we studied C57B6 mice as healthy control and nuclear erythroid factor-2 knockout (Nrf2-/-) male mice aged 4 and 12 months. Eleven-month-old wild-type and Nrf2-/- mice were fed with either standard diet or a diet containing 2.5% carbonyl-iron (iron overload [IO]) for 4 weeks. We show that Nrf2-/- mice develop an age-dependent cardiomyopathy, characterized by severe oxidation, degradation of SERCA2A and iron accumulation. This was associated with local hepcidin expression and increased serum non-transferrin-bound iron, which promotes maladaptive cardiac remodeling and interstitial fibrosis related to overactivation of the TGF-b pathway. When mice were exposed to IO diet, the absence of Nrf2 was paradoxically protective against further heart iron accumulation. Indeed, the combination of prolonged oxidation and the burst induced by IO diet resulted in activation of the unfolded protein response (UPR) system, which in turn promotes hepcidin expression independently from heart iron accumulation. In the heart of Hbbth3/+ mice, a model of b-thalassemia intermedia, despite the activation of Nrf2 pathway, we found severe protein oxidation, activation of UPR system and cardiac fibrosis independently from heart iron content. We describe the dual role of Nrf2 when aging is combined with IO and its novel interrelation with UPR system to ensure cell survival. We open a new perspective for early and intense treatment of cardiomyopathy in patients with b-thalassemia before the appearance of heart iron accumulation.

Preclinical Models of Cancer Therapy-Associated Cardiovascular Toxicity: A Scientific Statement From the American Heart Association.

Although cardiovascular toxicity from traditional chemotherapies has been well recognized for decades, the recent explosion of effective novel targeted cancer therapies with cardiovascular sequelae has driven the emergence of cardio-oncology as a new clinical and research field. Cardiovascular toxicity associated with cancer therapy can manifest as a broad range of potentially life-threatening complications, including heart failure, arrhythmia, myocarditis, and vascular events. Beyond toxicology, the intersection of cancer and heart disease has blossomed to include discovery of genetic and environmental risk factors that predispose to both. There is a pressing need to understand the underlying molecular mechanisms of cardiovascular toxicity to improve outcomes in patients with cancer. Preclinical cardiovascular models, ranging from cellular assays to large animals, serve as the foundation for mechanistic studies, with the ultimate goal of identifying biologically sound biomarkers and cardioprotective therapies that allow the optimal use of cancer treatments while minimizing toxicities. Given that novel cancer therapies target specific pathways integral to normal cardiovascular homeostasis, a better mechanistic understanding of toxicity may provide insights into fundamental pathways that lead to cardiovascular disease when dysregulated. The goal of this scientific statement is to summarize the strengths and weaknesses of preclinical models of cancer therapy-associated cardiovascular toxicity, to highlight overlapping mechanisms driving cancer and cardiovascular disease, and to discuss opportunities to leverage cardio-oncology models to address important mechanistic questions relevant to all patients with cardiovascular disease, including those with and without cancer.

It Takes Two to Tango! Protein-Protein Interactions behind cAMP-Mediated CFTR Regulation.

Over the last fifteen years, with the approval of the first molecular treatments, a breakthrough era has begun for patients with cystic fibrosis (CF), the rare genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). These molecules, known as CFTR modulators, have led to unprecedented improvements in the lung function and quality of life of most CF patients. However, the efficacy of these drugs is still suboptimal, and the clinical response is highly variable even among individuals bearing the same mutation. Furthermore, not all patients carrying rare CFTR mutations are eligible for CFTR modulator therapies, indicating the need for alternative and/or add-on therapeutic approaches. Because the second messenger 3',5'-cyclic adenosine monophosphate (cAMP) represents the primary trigger for CFTR activation and a major regulator of different steps of the life cycle of the channel, there is growing interest in devising ways to fine-tune the cAMP signaling pathway for therapeutic purposes. This review article summarizes current knowledge regarding the role of cAMP signalosomes, i.e., multiprotein complexes bringing together key enzymes of the cAMP pathway, in the regulation of CFTR function, and discusses how modulating this signaling cascade could be leveraged for therapeutic intervention in CF.

Emerging Roles of Phospholipase C Beta Isozymes as Potential Biomarkers in Cardiac Disorders.

Phospholipase C (PLC) enzymes represent crucial participants in the plasma membrane of mammalian cells, including the cardiac sarcolemmal (SL) membrane of cardiomyocytes. They are responsible for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) into 1,2-diacylglycerol (DAG) and inositol (1,4,5) trisphosphate (Ins(1,4,5)P3), both essential lipid mediators. These second messengers regulate the intracellular calcium (Ca2+) concentration, which activates signal transduction cascades involved in the regulation of cardiomyocyte activity. Of note, emerging evidence suggests that changes in cardiomyocytes' phospholipid profiles are associated with an increased occurrence of cardiovascular diseases, but the underlying mechanisms are still poorly understood. This review aims to provide a comprehensive overview of the significant impact of PLC on the cardiovascular system, encompassing both physiological and pathological conditions. Specifically, it focuses on the relevance of PLCß isoforms as potential cardiac biomarkers, due to their implications for pathological disorders, such as cardiac hypertrophy, diabetic cardiomyopathy, and myocardial ischemia/reperfusion injury. Gaining a deeper understanding of the mechanisms underlying PLCß activation and regulation is crucial for unraveling the complex signaling networks involved in healthy and diseased myocardium. Ultimately, this knowledge holds significant promise for advancing the development of potential therapeutic strategies that can effectively target and address cardiac disorders by focusing on the PLCß subfamily.

A non-catalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage.

Arterial remodeling in hypertension and intimal hyperplasia involves inflammation and disrupted flow, both of which contribute to smooth muscle cell dedifferentiation and proliferation. In this context, our previous results identified phosphoinositide 3-kinase γ (PI3Kγ) as an essential factor in inflammatory processes of the arterial wall. Here, we identify for the first time a kinase-independent role of nonhematopoietic PI3Kγ in the vascular wall during intimal hyperplasia using PI3Kγ-deleted mice and mice expressing a kinase-dead version of the enzyme. Moreover, we found that the absence of PI3Kγ in vascular smooth muscle cells (VSMCs) leads to modulation of cell proliferation, associated with an increase in intracellular cAMP levels. Real-time analysis of cAMP dynamics revealed that PI3Kγ modulates the degradation of cAMP in primary VSMCs independently of its kinase activity through regulation of the enzyme phosphodiesterase 4. Importantly, the use of an N-terminal competing peptide of PI3Kγ blocked primary VSMC proliferation. These data provide evidence for a kinase-independent role of PI3Kγ in arterial remodeling and reveal novel strategies targeting the docking function of PI3Kγ for the treatment of cardiovascular diseases.

Neurotoxic Effect of Doxorubicin Treatment on Cardiac Sympathetic Neurons.

Doxorubicin (DOXO) remains amongst the most commonly used anti-cancer agents for the treatment of solid tumors, lymphomas, and leukemias. However, its clinical use is hampered by cardiotoxicity, characterized by heart failure and arrhythmias, which may require chemotherapy interruption, with devastating consequences on patient survival and quality of life. Although the adverse cardiac effects of DOXO are consolidated, the underlying mechanisms are still incompletely understood. It was previously shown that DOXO leads to proteotoxic cardiomyocyte (CM) death and myocardial fibrosis, both mechanisms leading to mechanical and electrical dysfunction. While several works focused on CMs as the culprits of DOXO-induced arrhythmias and heart failure, recent studies suggest that DOXO may also affect cardiac sympathetic neurons (cSNs), which would thus represent additional cells targeted in DOXO-cardiotoxicity. Confocal immunofluorescence and morphometric analyses revealed alterations in SN innervation density and topology in hearts from DOXO-treated mice, which was consistent with the reduced cardiotropic effect of adrenergic neurons in vivo. Ex vivo analyses suggested that DOXO-induced denervation may be linked to reduced neurotrophic input, which we have shown to rely on nerve growth factor, released from innervated CMs. Notably, similar alterations were observed in explanted hearts from DOXO-treated patients. Our data demonstrate that chemotherapy cardiotoxicity includes alterations in cardiac innervation, unveiling a previously unrecognized effect of DOXO on cardiac autonomic regulation, which is involved in both cardiac physiology and pathology, including heart failure and arrhythmias.

Cardiac Overexpression of PDE4B Blunts ß-Adrenergic Response and Maladaptive Remodeling in Heart Failure.

BACKGROUND: The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac ß-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. METHODS: We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. RESULTS: PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but ß-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca2+ current, Ca2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (1012 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. CONCLUSIONS: Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.

Understanding the heart-brain axis response in COVID-19 patients: A suggestive perspective for therapeutic development.

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches.

Metabolic Aspects of Anthracycline Cardiotoxicity.

OPINION STATEMENT: Heart failure (HF) is increasingly recognized as the major complication of chemotherapy regimens. Despite the development of modern targeted therapies such as monoclonal antibodies, doxorubicin (DOXO), one of the most cardiotoxic anticancer agents, still remains the treatment of choice for several solid and hematological tumors. The insurgence of cardiotoxicity represents the major limitation to the clinical use of this potent anticancer drug. At the molecular level, cardiac side effects of DOXO have been associated to mitochondrial dysfunction, DNA damage, impairment of iron metabolism, apoptosis, and autophagy dysregulation. On these bases, the antioxidant and iron chelator molecule, dexrazoxane, currently represents the unique FDA-approved cardioprotectant for patients treated with anthracyclines.A less explored area of research concerns the impact of DOXO on cardiac metabolism. Recent metabolomic studies highlight the possibility that cardiac metabolic alterations may critically contribute to the development of DOXO cardiotoxicity. Among these, the impairment of oxidative phosphorylation and the persistent activation of glycolysis, which are commonly observed in response to DOXO treatment, may undermine the ability of cardiomyocytes to meet the energy demand, eventually leading to energetic failure. Moreover, increasing evidence links DOXO cardiotoxicity to imbalanced insulin signaling and to cardiac insulin resistance. Although anti-diabetic drugs, such as empagliflozin and metformin, have shown interesting cardioprotective effects in vitro and in vivo in different models of heart failure, their mechanism of action is unclear, and their use for the treatment of DOXO cardiotoxicity is still unexplored.This review article aims at summarizing current evidence of the metabolic derangements induced by DOXO and at providing speculations on how key players of cardiac metabolism could be pharmacologically targeted to prevent or cure DOXO cardiomyopathy.

The Interplay Between Autophagy and Senescence in Anthracycline Cardiotoxicity.

PURPOSE OF REVIEW: Doxorubicin (DOXO) is a highly effective chemotherapeutic drug employed for the treatment of a wide spectrum of cancers, spanning from solid tumours to haematopoietic malignancies. However, its clinical use is hampered by severe and dose-dependent cardiac side effects that ultimately lead to heart failure (HF). RECENT FINDINGS: Mitochondrial dysfunction and oxidative stress are well-established mechanisms of DOXO-induced cardiotoxicity, although recent evidence suggests that deregulation of other biological processes, like autophagy, could be involved. It is increasingly recognized that autophagy deregulation is intimately interconnected with the initiation of detrimental cellular responses, including autosis and senescence, raising the possibility of using autophagy modulators as well as senolytics and senomorphics for preventing DOXO cardiotoxicity. This review aims at providing an overview of the signalling pathways that are common to autophagy and senescence, with a special focus on how the relationship between these two processes is deregulated in response to cardiotoxic treatments. Finally, we will discuss the potential therapeutic utility of drugs modulating autophagy and/or senescence for counteracting DOXO cardiotoxicity.

Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches.

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.

Mechanisms underlying the cross-talk between heart and cancer.

Cardiovascular diseases and cancer remain the leading cause of death worldwide. Despite the fact that these two conditions have long been considered as distinct clinical entities, recent epidemiological and experimental studies suggest that they should be contemplated and treated as co-morbidities. Heart failure represents nowadays a well-established complication of cancer, primarily as a consequence of the aggressive use of cardiotoxic anti-cancer treatments. On the other hand, the provocative idea that heart failure can prime carcinogenesis has started to emerge, though the molecular basis is still to be fully elucidated. This review summarizes the current knowledge on the mechanisms underlying the bidirectional communication between the failing heart and the cancer. We will discuss and/or speculate on the role of molecular mediators released by either the tumour or the heart that can potentially link heart failure and cancer.

Potential therapeutic applications of AKAP disrupting peptides.

The 3'-5'-cyclic adenosine monophosphate (cAMP)/PKA pathway represents a major target for pharmacological intervention in multiple disease conditions. Although the last decade saw the concept of highly compartmentalized cAMP/PKA signaling consolidating, current means for the manipulation of this pathway still do not allow to specifically intervene on discrete cAMP/PKA microdomains. Since compartmentalization is crucial for action specificity, identifying new tools that allow local modulation of cAMP/PKA responses is an urgent need. Among key players of cAMP/PKA signaling compartmentalization, a major role is played by A-kinase anchoring proteins (AKAPs) that, by definition, anchor PKA, its substrates and its regulators within multiprotein complexes in well-confined subcellular compartments. Different tools have been conceived to interfere with AKAP-based protein-protein interactions (PPIs), and these primarily include peptides and peptidomimetics that disrupt AKAP-directed multiprotein complexes. While these molecules have been extensively used to understand the molecular mechanisms behind AKAP function in pathophysiological processes, less attention has been devoted to their potential application for therapy. In this review, we will discuss how AKAP-based PPIs can be pharmacologically targeted by synthetic peptides and peptidomimetics.

Cancer Risk in the Heart Failure Population: Epidemiology, Mechanisms, and Clinical Implications.

PURPOSE OF REVIEW: Along with population aging, the incidence of both heart failure (HF) and cancer is increasing. However, little is known about new-onset cancer in HF patients. This review aims at showing recent discoveries concerning this subset of patients. RECENT FINDINGS: Not only cancer and HF share similar risk factors but also HF itself can stimulate cancer development. Some cytokines produced by the failing heart induce mild inflammation promoting carcinogenesis, as it has been recently suggested by an experimental model of HF in mice. The incidence of new-onset cancer is higher in HF patients compared to the general population, and it significantly worsens their prognosis. Moreover, the management of HF patients developing new-onset cancer is challenging, especially due to the limited therapeutic options for patients affected by both cancer and HF and the higher risk of cardiotoxicity from anticancer drugs.

cAMP/PKA signaling compartmentalization in cardiomyocytes: Lessons from FRET-based biosensors.

3',5'-cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger produced in response to the stimulation of G protein-coupled receptors (GPCRs). It regulates a plethora of pathophysiological processes in different organs, including the cardiovascular system. It is now clear that cAMP is not uniformly distributed within cardiac myocytes but confined in specific subcellular compartments where it modulates key players of the excitation-contraction coupling as well as other processes including gene transcription, mitochondrial homeostasis and cell death. This review will cover the major cAMP microdomains in cardiac myocytes. We will describe recent work using pioneering tools developed for investigating the organization and the function of the major cAMP microdomains in cardiomyocytes, including the plasma membrane, the sarcoplasmic reticulum, the myofilaments, the nucleus and the mitochondria.

Phosphoinositide 3-Kinase Gamma Inhibition Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth.

BACKGROUND: Anthracyclines, such as doxorubicin (DOX), are potent anticancer agents for the treatment of solid tumors and hematologic malignancies. However, their clinical use is hampered by cardiotoxicity. This study sought to investigate the role of phosphoinositide 3-kinase γ (PI3Kγ) in DOX-induced cardiotoxicity and the potential cardioprotective and anticancer effects of PI3Kγ inhibition. METHODS: Mice expressing a kinase-inactive PI3Kγ or receiving PI3Kγ-selective inhibitors were subjected to chronic DOX treatment. Cardiac function was analyzed by echocardiography, and DOX-mediated signaling was assessed in whole hearts or isolated cardiomyocytes. The dual cardioprotective and antitumor action of PI3Kγ inhibition was assessed in mouse mammary tumor models. RESULTS: PI3Kγ kinase-dead mice showed preserved cardiac function after chronic low-dose DOX treatment and were protected against DOX-induced cardiotoxicity. The beneficial effects of PI3Kγ inhibition were causally linked to enhanced autophagic disposal of DOX-damaged mitochondria. Consistently, either pharmacological or genetic blockade of autophagy in vivo abrogated the resistance of PI3Kγ kinase-dead mice to DOX cardiotoxicity. Mechanistically, PI3Kγ was triggered in DOX-treated hearts, downstream of Toll-like receptor 9, by the mitochondrial DNA released by injured organelles and contained in autolysosomes. This autolysosomal PI3Kγ/Akt/mTOR/Ulk1 signaling provided maladaptive feedback inhibition of autophagy. PI3Kγ blockade in models of mammary gland tumors prevented DOX-induced cardiac dysfunction and concomitantly synergized with the antitumor action of DOX by unleashing anticancer immunity. CONCLUSIONS: Blockade of PI3Kγ may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth.