The dual effects of miR-222 in cardiac hypertrophy: bridging pathological and physiological paradigms

This editorial refers to ‘miR-222 inhibits pathological cardiac hypertrophy and heart failure’, by X. Liu et al., https://doi.org/10.1093/cvr/cvad184.

1. Cardiac hypertrophy: a tale of exercise and disease

At the beginning of our exploration into the multifaceted nature of cardiac hypertrophy, let us consider two distinct yet interconnected scenarios. First, we focus on professional athletes who, as part of their routine health assessments, undergo extensive cardiac screening. This screening includes echocardiograms, which can visualize the heart’s structural adaptations to increased physical demands. It is not uncommon in such assessments to diagnose physiological cardiac hypertrophy. This condition, characterized by the enlargement of the heart muscle, occurs as an adaptive response to various stimuli, including intense physical exercise, developmental growth, and pregnancy. On the other hand, there is a contrasting case of individuals living with chronic high blood pressure. During standard cardiac evaluations often performed to monitor hypertension, they might discover they have developed pathological cardiac hypertrophy. This form of hypertrophy, which leads to unfavourable modifications in cardiac structure, can also occur in patients with conditions causing pressure overload, such as aortic stenosis. Diagnostic tests in these patients, such as echocardiograms, often reveal changes like the thickening of the left ventricular wall, a hallmark of the heart’s struggle against elevated blood pressure. These two examples, representing the spectrum of cardiac hypertrophy, set the stage for our deeper dive into the intricate mechanisms and implications of this complex condition. Indeed, physiological and pathological hypertrophy are regulated by distinct pathways.^1,2 Therefore, understanding the nuanced mechanisms that differentiate these two forms is crucial for developing targeted therapies.

2. Mechanistic insights: miR-222 at the crossroads

miRNAs (miRNAs, miRs) offer promising avenues for targeted therapeutic strategies due to their ability to downregulate targets that are integral in health and disease. Numerous studies have shown that miRNAs play essential roles in cardiovascular diseases regulating a plethora of processes including cardiomyocyte survival,³ proliferation,⁴ and angiogenesis.⁵ In the context of cardiac hypertrophy, miR-222 appears to be of critical importance due to its dual effects, orchestrating pathways in both physiological and pathological conditions. In 2015, Liu et al. demonstrated that miR-222 is upregulated in exercise-induced hypertrophy and its inhibition blocks the adaptive cardiac and cardiomyocyte growth. Interestingly, the authors identified four targets of miR-222 that are potentially relevant to this hypertrophic response: p27, a gene encoding a cell-cycle inhibitor; Hipk1 and Hipk2, encoding protein kinases and the transcriptional repressor Hmbox1 (Figure 1).⁶ Thus, this study demonstrated that the upregulation of miR-222 is crucial for the adaptive hypertrophic process in response to exercise.

Figure 1.

The dual effects of miR-222 under exercise- and pressure overload-induced hypertrophy. miRNA-222 is upregulated in physiological cardiac-induced hypertrophy following exercise and pathological cardiac-induced hypertrophy following TAC. Under physiological hypertrophy, miRNA inhibition blocks cardiac and cardiomyocyte growth, suggesting a role in physiological cardiac growth. Following TAC, miRNA inhibition accelerates pathological hypertrophy, cardiac dysfunction, and heart failure, while miRNA cardiac-specific expression attenuates pathological hypertrophy, cardiac function, and survival suggesting a role in the inhibition of pathological cardiac growth. The figure represents validated targets of miR-222 in each scenario. The figure was created with BioRender.com.

Conversely, in their recent work published in this issue of Cardiovascular Research, Liu et al. have shown that in the setting of pathological hypertrophy, miR-222 presents a different scenario.⁷ In this form of hypertrophy, miR-222 emerges as a factor that is inhibiting pathological cardiac growth. To induce pathological hypertrophy, the authors employed a transverse aortic constriction (TAC) mouse model. This model mimics the pressure overload seen in conditions including hypertension, providing invaluable insights into the heart’s response to chronic stress. In line with physiological hypertrophy, miR-222 was upregulated at 7 and 14 days following TAC, concurrently with an observed increase in heart weight to tibial length ratios which indicated hypertrophy induction. Interestingly, miRNA inhibition using locked nucleic acid anti-miR-222 (LNA-anti-miR-222) increased cardiac mass, cardiomyocyte size, and apoptosis compared to control anti-miR-treated animals suggesting that miR-222 upregulation observed following TAC helps attenuate the development of pathological hypertrophy and the progression to heart failure. Importantly, cardiac-specific upregulation of miR-222 not only improved cardiac function and reduced cardiomyocyte hypertrophy but also decreased lung weight, which is a key indicator of heart failure, and mitigated fibrosis and apoptosis. In both gain- and loss-of-function models, the cardiac structure and function were observed to be normal at baseline conditions. Finally, profiling of potential miR-222 targets after TAC yielded a distinct set of genes compared to the model of exercise-induced hypertrophy. This included p53 upregulated modulator of apoptosis, a pro-apoptotic Bcl-2 family member, and the transcription factor NFATc3, as well as Hmbox1 which was also identified as a miR-222 target in the exercise-induced hypertrophy model (Figure 1).⁷ Overall, these findings support the pivotal role of miR-222 in both exercise- and pressure overload-induced hypertrophy, underscoring the complexity of cardiac regulatory mechanisms and highlighting its potential as a therapeutic target in diverse cardiac conditions.

3. Beyond miR-222: exploring the dual effects of miRNAs in cardiac function

The study of Liu et al. extends our understanding of miRNA function in physiological and pathological cardiac growth, providing a new lens to view the complex nature of cardiac hypertrophy. The concept of miRNAs having a context-dependent role in cardiac function is further elucidated, by the work of Smolka et al., who investigated the role of miR-100 in cardiac function under pressure overload. Their study demonstrated that cardiomyocyte-specific overexpression of miR-100 in mice does not alter the cardiac structure and function under normal conditions. However, under pressure overload, miR-100 overexpression attenuates maladaptive cardiac remodelling, preserving heart function.⁸ Further adding to this narrative is the study of Zhang et al. on miR-320. In their work, the authors demonstrated that the effect of miR-320 in heart failure is highly context-dependent: while overexpression of miR-320 in cardiomyocytes exacerbates cardiac dysfunction, its upregulation in cardiac fibroblasts is protective, alleviating cardiac fibrosis and hypertrophy.⁹ Such findings underscore the nuanced nature of miRNA action within different cardiac cell types and conditions. The dual effects of miR-222, the protective role of miR-100, and the differential impact of miR-320 underscore the need for precision in targeting miRNAs for therapeutic purposes.

4. miR-222: a therapeutic target?

Building on these insights, the role of miR-222 in the setting of pressure overload emerges as particularly significant. Not only does miR-222 upregulate in response to such stress, but it also serves as a mitigating factor, slowing down the progression to heart failure. The study’s revelation that miR-222 overexpression can protect against TAC-induced heart failure without affecting baseline heart function is of therapeutic interest. It suggests a potential intervention that remains inactive under normal conditions and activates only in counteracting pathological stress. This important characteristic of miR-222 could pave the way for novel treatments targeting heart failure, a leading cause of morbidity and mortality globally,¹⁰ offering a promising approach to address one of the most pressing challenges in cardiovascular medicine. However, the opposing results observed in the different contexts underscore the importance of conducting in-depth mechanistic and observational studies, alongside ensuring the safety of miRNA dosing.

5. Conclusion

In conclusion, the study presents a compelling case for the multifaceted role of miR-222 in cardiac hypertrophy. It not only enhances our understanding of the molecular underpinnings of heart disease but also opens new avenues for precise therapeutic exploration. The distinction between exercise- and pressure overload-induced cardiac hypertrophy, mediated by a single miRNA, epitomizes the complexity of cardiac physiology and pathological conversion. With this knowledge, we step closer to opening new doors for the treatment and management of cardiac diseases.

Funding

D.K. is supported by the European Union Horizon 2020 CardioReGenix (grant no. 825670). A.B. is supported by the British Heart Foundation (grant no. CH/11/2/28733). A.H.B. is supported by the European Union Horizon 2020 CardioReGenix (grant no. 825670) and the British Heart Foundation (grant no. CH/11/2/28733; CRMR/21/290009).