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Phenotypic Screening with Deep Learning Identifies HDAC6 Inhibitors as Cardioprotective Agents in Mouse Models of Dilated Cardiomyopathy

ABSTRACT: Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of heart failure, driving a need to develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) deficient in BCL2-associated athanogene 3 (BAG3). With these BAG3-deficient iPSC-CMs, we identified cardioprotective drugs with a phenotypic screen and deep learning. Using a library of 5500 bioactive compounds and siRNA validation, we identified that inhibiting histone deacetylase 6 (HDAC6) was cardioprotective at the sarcomere level. We translated this finding to a BAG3 cardiac-knockout (BAG3cKO) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function. In BAG3cKO and BAG3 E455K mice, HDAC6 inhibitors improved left ventricular ejection fraction and reduced left ventricular diameter at diastole and systole. We also found that HDAC6 inhibitors protected the microtubule network from mechanical damage, increased autophagic flux, decreased apoptosis, and reduced inflammation in the heart. Our results demonstrate the power of combining iPSC-CMs with phenotypic screening and deep learning to accelerate target and drug discovery, and they support the development of novel therapies that address underlying mechanisms associated with heart disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE179656 | GEO | 2021/12/31

REPOSITORIES: GEO

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Project description:Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by left ventricular or biventricular dilation and systolic dysfunction. It presents one of the most common causes of heart failure worldwide and also the most common indication for heart transplantation. Despite the discharge treatment possibilities, the outcome of patients with recent onset DCM often remains unpredictable and major adverse events may occur in the first months following the diagnosis. Enhancement in the left ventricular ejection fraction – designed as the left ventricular reverse remodeling (LVRR) – has been considered one of the most important determinants of the improvement and treatment response in the prognosis of DCM. In the present study we performed a comprehensive quantitative proteomic analysis of DCM patients’ plasma samples. First we searched for the differences against healthy control group and found several proteins and biological processes to be significantly regulated. The most DCM up-regulated terms corresponded to inflammatory response, wound healing and complement. Among the most relevant DCM up-regulated proteins were CRP, CD163, AOC3, PF4, IGF2, IGFBP2 and TNC. Down-regulation in DCM samples was observed in the biological processes of blood coagulation and lipid metabolism, both of which present risk factors in cardiovascular diseases. The most relevant down-regulated proteins in DCM were TTN, GSN, FCN3, PON1, PON3, and COMP. In the second part of the study, we observed the clinical fate of the DCM patients one year after admission. We divided them according to their treatment response into subgroups of responders (LVRR+) and non-responders (LVRR-) and searched for proteins that would help to predict the patient’s fate or to elucidate the molecular consequences of the disease progression. The protein with the best prognostic potential was ALDOB, its elevated plasma level was found in patients with worse or fatal outcome. The patients with no or poor treatment response had also up-regulated immunoglobulins and pathways corresponding to immunoglobulin-mediated immune response together with cell adhesion which points to the importance of these processes in the DCM pathology.

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Phenotypic Screening with Deep Learning Identifies HDAC6 Inhibitors as Cardioprotective Agents in Mouse Models of Dilated Cardiomyopathy

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