Targeting the cytoskeleton and extracellular matrix in cardiovascular disease drug discovery

ABSTRACT

Introduction

Currently, cardiovascular disease (CVD) drug discovery has focused primarily on addressing the inflammation and immunopathology aspects inherent to various CVD phenotypes such as cardiac fibrosis and coronary artery disease. However, recent findings suggest new biological pathways for cytoskeletal and extracellular matrix (ECM) regulation across diverse CVDs, such as the roles of matricellular proteins (e.g. tenascin-C) in regulating the cellular microenvironment. The success of anti-inflammatory drugs like colchicine, which targets microtubule polymerization, further suggests that the cardiac cytoskeleton and ECM provide prospective therapeutic opportunities.

Areas covered

Potential therapeutic targets include proteins such as gelsolin and calponin 2, which play pivotal roles in plaque development. This review focuses on the dynamic role that the cytoskeleton and ECM play in CVD pathophysiology, highlighting how novel target discovery in cytoskeletal and ECM-related genes may enable therapeutics development to alter the regulation of cellular architecture in plaque formation and rupture, cardiac contractility, and other molecular mechanisms.

Expert opinion

Further research into the cardiac cytoskeleton and its associated ECM proteins is an area ripe for novel target discovery. Furthermore, the structural connection between the cytoskeleton and the ECM provides an opportunity to evaluate both entities as sources of potential therapeutic targets for CVDs.

KEYWORDS:

• Cardioinformatics
• computational biology
• drug discovery
• precision medicine
• therapeutics

Article highlights

• Previous CVD studies indicate relationships between ECM proteins and the disruption of the cytoskeletal architecture.

• Observed changes in cellular architecture during cardiovascular health-to-disease transitions indicate the cytoskeleton/ECM is likely dysregulated.

• A cardioinformatics analysis of cytoskeletal/ECM-related genes may reveal new therapeutic modalities.

• Mechanisms behind existing therapeutics provide support for targeting cytoskeletal/ECM biology at different CVD development stages.

• Refining computational analytical techniques for drug discovery over the next five, ten or so years is essential for increasing the probability of success and help to decrease risk in drug development.

This box summarizes key points contained in the article.

ABBREVIATIONS

CAD, coronary artery disease; CAVD, calcific aortic valve disease; CVD, cardiovascular disease; CRT, cardiac resynchronization therapy; ECM, extracellular matrix; DHF, dyssynchronous heart failure; CRT, cardiac resynchronization therapy; MMP, matrix metalloproteinase; TSP, thrombospondin; OPN, osteopontin; TGF, transforming growth factor; ACS, acute coronary syndrome; DGC, dystrophin glycoprotein complex; EGFR, epidermal growth factor receptor; eQTL, expression quantitative trait loci; SNP, single nucleotide polymorphism; GWAS, genome-wide association study; LVOT, left ventricular outflow tract; LTBP, Latent TGF-β binding protein; pVO₂, mixed venous oxygen tension; VSMC, vascular smooth muscle cell; VCL, vinculin isoform 2; ILK, integrin linked kinase; CHAP, cytoskeletal heart-enriched actin-associated protein; OM, omecamtiv mecarbil; PAH, pulmonary arterial hypertension; mRNA, messenger ribonucleic acid; mRNA-seq, messenger ribonucleic acid sequencing; ApoE, apolipoprotein E; MI, myocardial infarction; HDAC, histone deacetylase; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; BMP, bone morphogenetic protein; HDACi, HDAC inhibitors; DNMT1, DNA methyltransferases 1; αSMA, α-smooth muscle actin; HHT, hereditary hemorrhagic telangiectasia; HDACi, HDAC inhibitor

Declaration of interest

BB Khomtchouk is the co-founder of Dock Therapeutics, Inc. MH Davidson is the co-founder of New Amsterdam Pharma B.V. and Dock Therapeutics, Inc. MH Davidson is also the former co-founder of Omthera Pharmaceuticals, Inc. (acquired by AstraZeneca) and Corvidia Therapeutics, Inc. (acquired by Novo Nordisk). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are supported through the University of Chicago Center for Translational Data Science (CTDS) Pilot Award and National Institutes of Health grant K12HL143959 awarded to BB Khomtchouk. The authors also acknowledge that ML Khan is supported by the University of Chicago Micro-Metcalf Program while YS Lee is supported by the University of Chicago 2020-2021 Jeff Metcalf Fellowship Program and the 2021 Move Forward, Give Back Fellowship Program.