Jeswin Vennatt

Introduction.  When the heart undergoes stress stimulation such as a myocardial infarction or pressure overload, it undergoes hypertrophic growth.¹ This initial cardiac remodeling is so that the heart can match the increase in stress, however, it is also the primary reason for heart failure.¹ Cardiac hypertrophy is heavily regulated by gene expression and the production of select proteins in cardiomyocytes.¹ Cardiac failure is a multifactorial condition that has areas of possible intervention at mechanistic, cellular, and substrate levels. This allows for multiple methods of intervention that could be conducted simultaneously resulting in varying degrees of effectiveness.⁵ Due to the high rates of cardiac failure associated with cardiac hypertrophy, medical interventions that target the regulation of cardiac hypertrophy could prove to be promising treatment method. Methods. Primary cardiomyocytes were isolated and m6A immunoprecipitation and RNA sequencing was conducted on them. METTL3 was then used to modulate the m6A levels in the cardiomyocytes in both culture and in vivo. The gain and loss of function was then observed in mouse models to assess m6A’s role in cardiac function and homeostasis. Results. The study showed that m6A methylation played a role in mediating hypertrophic stimuli and was a normal response in cardiomyocytes. Increased m6A resulted in a stronger response to hypertrophy while a decreased m6A resulted in dysfunction and irregular cardiomyocyte remodeling. Conclusions. The study demonstrates that m6A serves as a crucial stress-response mechanism in the heart in order to maintain normal function. It can also serve as a possible area of therapy for patients who may have reduced m6A function or hyperactive m6A function in relation to cardiac hypertrophy. Cardiac hypertrophy and cardiac remodeling are necessary adaptations in heart function; however, they can also lead to heart failure. This incentivizes clinicians and scientists to identify methods to regulate cardiac hypertrophy.¹There are many methods to clinically intervene on cardiac hypertrophy. Some methods such as M6A, HINT1, and mTOR work on a mechanistic level in regulating cardiac hypertrophy.^1,3,4 Other methods prioritize specific substrate usage in order to regulate cardiac hypertrophy.² Methods such as targeting macrophage activation and subtype class switching have also shown to be effective in treating cardiac hypertrophy.⁵ Although these methods of regulating cardiac hypertrophy have been tested individually, future studies may show that a combination of two or more of these methods may have an additive affect in the treatment of heart failure and cardiac hypertrophy.

1.  Dorn LE, Lasman L, Chen J, et al. The N⁶-Methyladenosine mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy. Circulation. 2019;139(4):533-545. doi:10.1161/CIRCULATIONAHA.118.036146
2. Ritterhoff J, Young S, Villet O, et al. Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis. Circ Res. 2020;126(2):182-196. doi:10.1161/CIRCRESAHA.119.315483
3.  Zhang Y, Da Q, Cao S, et al. HINT1 (Histidine Triad Nucleotide-Binding Protein 1) Attenuates Cardiac Hypertrophy Via Suppressing HOXA5 (Homeobox A5) Expression. Circulation. 2021;144(8):638-654. doi:10.1161/CIRCULATIONAHA.120.051094
4. Liu R, Zhang HB, Yang J, Wang JR, Liu JX, Li CL. Curcumin alleviates isoproterenol-induced cardiac hypertrophy and fibrosis through inhibition of autophagy and activation of mTOR. Eur Rev Med Pharmacol Sci. 2018;22(21):7500-7508. doi:10.26355/eurrev_201811_16291
5. Ren Z, Yu P, Li D, et al. Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac Hypertrophy. Circulation. 2020;141(21):1704-1719. doi:10.1161/CIRCULATIONAHA.119.043053