lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• RNA Biology

Background:

• Cardiac growth occurs in response to physiological and pathological stimuli, with differing outcomes.
• Physiological hypertrophy protects the heart, while pathological hypertrophy can lead to heart failure.
• The roles of long noncoding RNAs (lncRNAs) in physiological cardiac growth remain largely unknown.

Purpose of the Study:

• To investigate the role of lncRNAs in exercise-induced physiological cardiac hypertrophy and cardiomyogenesis.
• To identify novel molecular pathways regulating the switch between physiological and pathological cardiac growth.

Main Methods:

• RNA sequencing of mouse hearts subjected to exercise or transverse aortic constriction.
• Overexpression and inhibition of candidate lncRNAs using adeno-associated virus vectors and antisense locked nucleic acid-GapmeRs.
• Functional studies of downstream effectors, including DCHS2, in zebrafish and mice.

Main Results:

• Identified exercise-regulated cardiac lncRNAs (lncExACTs), with lncExACT1 showing opposing regulation in physiological vs. pathological conditions.
• lncExACT1 overexpression induced pathological hypertrophy and heart failure; inhibition promoted physiological hypertrophy and protected against fibrosis.
• The lncExACT1-DCHS2 pathway regulates microRNA-222, calcineurin, and Hippo/Yap1 signaling, controlling cardiac growth outcomes.

Conclusions:

• The lncExACT1-DCHS2 pathway is a novel regulator of cardiac hypertrophy and cardiomyogenesis.
• This pathway acts as a master switch, determining whether cardiac growth is beneficial or detrimental.
• Targeting the lncExACT1-DCHS2 pathway offers a potential therapeutic strategy for heart conditions.