Targeting of CAT and VCAM1 as Novel Therapeutic Targets for DMD Cardiomyopathy

Abstract

Duchenne muscular dystrophy (DMD) related cardiomyopathy is the leading cause of early mortality in DMD patients. There is an urgent need to gain a better understanding of the disease molecular pathogenesis and develop effective therapies to prevent the onset of heart failure. In the present study, we used DMD human induced pluripotent stem cells (DMD-hiPSCs) derived cardiomyocytes (CMs) as a platform to explore the active compounds in commonly used Chinese herbal medicine (CHM) herbs. Single CHM herb (DaH, ZK, and CQZ) reduced cell beating rate, decreased cellular ROS accumulation, and improved structure of DMD hiPSC-CMs. Cross-comparison of transcriptomic profiling data and active compound library identified nine active chemicals targeting ROS neutralizing Catalase (CAT) and structural protein vascular cell adhesion molecule 1 (VCAM1). Treatment with Quecetin, Kaempferol, and Vitamin C, targeting CAT, conferred ROS protection and improved contraction; treatment with Hesperidin and Allicin, targeting VCAM1, induced structure enhancement via induction of focal adhesion. Lastly, overexpression of CAT or VCAM1 in DMD hiPSC-CMs reconstituted efficacious effects and conferred increase in cardiomyocyte function. Together, our results provide a new insight in treating DMD cardiomyopathy via targeting of CAT and VCAM1, and serves as an example of translating Bed to Bench back to Bed using a muti-omics approach.

A Long-Term Study Evaluating the Effects of Nicorandil Treatment on Duchenne Muscular Dystrophy-Associated Cardiomyopathy in mdx Mice

“…46 Other treatments under investigation in the DMD heart include cell-based therapies and membrane sealants, which have shown promising results and are now in clinical trials. [47][48][49][50][51] Other agents being investigated for their ability to target specific cellular phenotypes have shown to stimulate nitric oxide (NO) signaling, 14,52,53 diminish oxidative stress, [54][55][56] preserve mitochondrial function 57 and downregulate cell death processes. 50,51 While these molecular treatments have shown promise in animal models of DMD, they have not yet led to clinical improvement in patients with DMD cardiomyopathy.…”

Proximal telomeric decompaction due to telomere shortening drives FOXC1-dependent myocardial senescence

“…Cells were regularly checked for mycoplasma contamination. Cardiac differentiation was performed at a confluency of 70–90% using an established protocol ( 33 ). Briefly, to initiate differentiation, hiPSC were treated with 4–6 μM CHIR-99021 (Selleck Chemicals) for 2 days and followed by a Wnt inhibitor IWR-1 treatment (5 μM; Sigma) for another 2 days, RPMI 1640 medium (Sigma) supplemented with B27 minus insulin (Thermo Fisher Scientific) was used as the basal medium.…”

Mitochondria and Reactive Oxygen Species: The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy

“…Catalase is a key enzyme of cellular oxidative balance and cellular redox signaling regulation, as it hydrolyzes the highly reactive hydrogen peroxide (H 2 O 2 ) into water and O2 [125]; therefore, it has been hypothesized that its overexpression would result in improved dystrophic skeletal muscle. Indeed, the overexpression of CAT improved the muscle function of mdx mice [126], as well as the cardiomyocyte function of DMD iPSC-derived cardiomyocytes [127]. HO-1 is responsible for the synthesis of biliverdin and bilirubin, which are non-enzymatic antioxidants present in skeletal muscle.…”