HDAC5 Inhibition as a Therapeutic Strategy for Titin Deficiency-Induced Cardiac Remodeling: Insights from Human iPSC...

Area of Science:

• Cardiovascular biology
• Epigenetics
• Genetic heart disease

Background:

• Dilated cardiomyopathy (DCM) is a major cause of heart failure, frequently linked to genetic variants in the titin (TTN) gene.
• The exact molecular pathways connecting TTN deficiency to cardiac dysfunction and fibrosis are not fully understood.
• Identifying epigenetic regulators is crucial for developing targeted therapies for TTN-related cardiomyopathies.

Purpose of the Study:

• To pinpoint epigenetic regulators of TTN-mediated gene expression in DCM.
• To investigate the therapeutic potential of targeting these regulators in TTN deficiency.

Main Methods:

• RNA sequencing analysis of human heart tissue from patients with DCM and other cardiomyopathies.
• Modeling TTN deficiency in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
• Evaluating the effects of TMP-195 (a class IIa histone deacetylase inhibitor) and specific HDAC knockdowns (HDAC4/5/7/9) on cardiac gene expression and fibrosis markers.

Main Results:

• TTN deficiency in patient data and iPSC-CMs led to reduced expression of cardiac function genes (MYH6, NPPA) and increased fibrosis-associated genes.
• TMP-195 treatment normalized NPPA and MYH6 expression and reduced collagen gene expression without affecting TTN levels.
• HDAC5 knockdown showed the most significant improvement in cardiac markers and fibrosis-related genes, with co-silencing of TTN and HDAC5 yielding similar benefits.

Conclusions:

• HDAC5 is identified as a critical epigenetic regulator in TTN deficiency-induced cardiac maladaptation.
• Pharmacological inhibition of HDAC5 using TMP-195 effectively reverses TTN-deficiency-associated gene dysregulation.
• These findings suggest TMP-195 has significant translational potential for treating TTN-related cardiomyopathies.