Non-canonical PPARα Agonism by Arjunolic Acid Mitigates Cardiomyocyte PANoptosis Through a Novel PPARα/CRYAB/IKKα Axis During Pathological Cardiac Hypertrophy.

This study was designed to investigate the expression of short-chain acyl-CoA dehydrogenase (SCAD), a key enzyme of fatty acid β-oxidation, during rat heart development and the difference of SCAD between pathological and physiological cardiac hypertrophy. The expression of SCAD was lowest in the foetal and neonatal heart, which had time-dependent increase during normal heart development. In contrast, a significant decrease in SCAD expression was observed in different ages of spontaneously hypertensive rats (SHR). On the other hand, swim-trained rats developed physiological cardiac hypertrophy, whereas SHR developed pathological cardiac hypertrophy. The two kinds of cardiac hypertrophy exhibited divergent SCAD changes in myocardial fatty acids utilization. In addition, the expression of SCAD was significantly decreased in pathological cardiomyocyte hypertrophy, however, increased in physiological cardiomyocyte hypertrophy. SCAD siRNA treatment triggered the pathological cardiomyocyte hypertrophy, which showed that the down-regulation of SCAD expression may play an important role in pathological cardiac hypertrophy. The changes in peroxisome proliferator-activated receptor α (PPARα) was accordant with that of SCAD. Moreover, the specific PPARα ligand fenofibrate treatment increased the expression of SCAD and inhibited pathological cardiac hypertrophy. Therefore, we speculate that the down-regulated expression of SCAD in pathological cardiac hypertrophy may be responsible for ‘the recapitulation of foetal energy metabolism’. The deactivation of PPARα may result in the decrease in SCAD expression in pathological cardiac hypertrophy. Changes in SCAD are different in pathological and physiological cardiac hypertrophy, which may be used as the molecular markers of pathological and physiological cardiac hypertrophy.

Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including alpha- and beta-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. These findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH receptors (TRs) beta1, alpha1, and alpha2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, alpha- and beta-MyHC and SERCA. All 3 TR subtypes in myocytes were downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, phenylephrine in culture and pressure overload in vivo. Myocyte TRbeta1 was upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfection and treatment with the TRbeta1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TRbeta1 to transcription of beta-MyHC, SERCA, and TRbeta1, and TRalpha1 to alpha-MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulation and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological and pathological cardiac hypertrophy.

Exercise-induced physiological hypertrophy provides protection against cardiovascular disease, whereas disease-induced pathological hypertrophy leads to heart failure. Emerging evidence suggests pleiotropic roles of melatonin in cardiac disease; however, the effects of melatonin on physiological vs pathological cardiac hypertrophy remain unknown. Using swimming-induced physiological hypertrophy and pressure overload-induced pathological hypertrophy models, we found that melatonin treatment significantly improved pathological hypertrophic responses accompanied by alleviated oxidative stress in myocardium but did not affect physiological cardiac hypertrophy and oxidative stress levels. As an important mediator of melatonin, the retinoid-related orphan nuclear receptor-α (RORα) was significantly decreased in human and murine pathological hypertrophic cardiomyocytes, but not in swimming-induced physiological hypertrophic murine hearts. In vivo and in vitro loss-of-function experiments indicated that RORα deficiency significantly aggravated pathological cardiac hypertrophy, and notably weakened the anti-hypertrophic effects of melatonin. Mechanistically, RORα mediated the cardioprotection of melatonin in pathological hypertrophy mainly by transactivation of manganese-dependent superoxide dismutase (MnSOD) via binding to the RORα response element located in the promoter region of the MnSOD gene. Furthermore, MnSOD overexpression reversed the pro-hypertrophic effects of RORα deficiency, while MnSOD silencing abolished the anti-hypertrophic effects of RORα overexpression in pathological cardiac hypertrophy. Collectively, our findings provide the first evidence that melatonin exerts an anti-hypertrophic effect on pathological but not physiological cardiac hypertrophy via alleviating oxidative stress through transactivation of the antioxidant enzyme MnSOD in a RORα-dependent manner.

] In fact, recent studies have demonstrated experimentally that increasing the burden of misfolded proteins in the heart can contribute to the development of cardiac dysfunction. In this review, we discuss the role of heat shock proteins (HSPs) in common cardiac diseases, including cardiac hypertrophy, heart failure, and ischemia/reperfusion injury. Furthermore, we delineate the many specific mechanisms by which these chaperones, cochaperones, and heat shock factor (HSF) transcription factors have been found to be cardioprotective in experimental models. Lastly, we review recent studies involving drugs that are being developed (and currently used) to increase the expression (and presumably function) of chaperone/cochaperone systems that may be applicable to the treatment of common cardiac diseases and familial cardiac diseases with a pathogenesis that includes a major component of misfolded proteins (eg, desminopathies).

Inhibition of pathological cardiac hypertrophy is recognized as an important therapeutic strategy for heart failure, although effective targets are still lacking in clinical practice. Homeodomain interacting protein kinase 1 (HIPK1) is a conserved serine/threonine kinase that can respond to different stress signals, however, whether and how HIPK1 regulates myocardial function is not reported. Here, it is observed that HIPK1 is increased during pathological cardiac hypertrophy. Both genetic ablation and gene therapy targeting HIPK1 are protective against pathological hypertrophy and heart failure in vivo. Hypertrophic stress‐induced HIPK1 is present in the nucleus of cardiomyocytes, while HIPK1 inhibition prevents phenylephrine‐induced cardiomyocyte hypertrophy through inhibiting cAMP‐response element binding protein (CREB) phosphorylation at Ser271 and inactivating CCAAT/enhancer‐binding protein β (C/EBPβ)‐mediated transcription of pathological response genes. Inhibition of HIPK1 and CREB forms a synergistic pathway in preventing pathological cardiac hypertrophy. In conclusion, HIPK1 inhibition may serve as a promising novel therapeutic strategy to attenuate pathological cardiac hypertrophy and heart failure.

Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies

IntroductionLeft ventricular hypertrophy (LVH) has proven to be a very useful risk marker in hypertension. It indicates a higher risk of cardiovascular events and particularly sudden death [1,2]. It defines the effects of hypertension on an important target organ, the heart, and is one step along th

See related article, pages 1164–1174 Cardiac hypertrophy is the natural response of myocardium to various stressors, including neurohormonal stimuli, hemodynamic overload, and injury. In the face of continued stress, pathological hypertrophy progresses to a loss of cardiomyocytes, the development of fibrosis, and, ultimately, heart failure. Emerging evidence has shown that glycogen synthase kinase-3β (GSK-3β) is an important negative regulator of cardiomyocyte hypertrophy, yet inhibition of GSK-3β has been shown to reduce cell death after ischemia reperfusion. Therefore, it has been difficult to predict what the consequences of chronic inhibition of GSK-3 in the heart would be because it might be a balance between the potential for the aggravation of cardiac hypertrophy versus antiapoptotic effects. In this issue of Circulation Research , Hirotani and colleagues report that sustained inhibition of GSK-3β in postneonatal hearts results in well-compensated “physiologic” cardiac hypertrophy and, most intriguingly, exerts protective effects against the development of “pathological” hypertrophy and heart failure with pressure overload.1 Although there are a number of concerns that need to be addressed before targeting GSK-3 for the treatment of heart failure, this “best of both worlds” outcome provides an interesting and favorable rationale for such intervention. The GSK-3 family of protein kinases is encoded by 2 genes, α and β. They are highly conserved throughout evolution and are critical to the regulation of diverse biological processes ranging from organ development to cell death, including cell growth, cell cycling, cytoskeletal organization, and metabolism.2,3 Furthermore, dysregulation of GSK-3β has been implicated in the pathogenesis of many human diseases including Alzheimer disease, diabetes, and tumorgenesis.4–8 GSK-3α (51 kDa) is the larger of the two and has a glycine-rich N terminus of unknown function. GSK-3β (47 kDa) and α share significant sequence homology (97%) in their kinase domains, however the homology between the …

Physiological cardiac hypertrophy occurs in response to exercise and can protect against pathological stress. In contrast, pathological hypertrophy occurs in disease and often precedes heart failure. The cardiac pathways activated in physiological and pathological hypertrophy are largely distinct. Our prior work demonstrated that miR-222 increases in exercised hearts and is required for exercise-induced cardiac hypertrophy and cardiomyogenesis. Here, we sought to define the role of miR-222 in pathological hypertrophy. We found that miR-222 also increased in pathological hypertrophy induced by pressure overload. To assess its functional significance in this setting, we generated a miR-222 gain-of-function model through cardiac-specific constitutive transgenic miR-222 expression (TgC-miR-222) and used locked nucleic acid anti-miR specific for miR-222 to inhibit its effects. Both gain- and loss-of-function models manifested normal cardiac structure and function at baseline. However, after transverse aortic constriction (TAC), miR-222 inhibition accelerated the development of pathological hypertrophy, cardiac dysfunction, and heart failure. Conversely, miR-222-overexpressing mice had less pathological hypertrophy after TAC, as well as better cardiac function and survival. We identified p53-up-regulated modulator of apoptosis, a pro-apoptotic Bcl-2 family member, and the transcription factors, Hmbox1 and nuclear factor of activated T-cells 3, as direct miR-222 targets contributing to its roles in this context. While miR-222 is necessary for physiological cardiac growth, it inhibits cardiac growth in response to pressure overload and reduces adverse remodelling and cardiac dysfunction. These findings support the model that physiological and pathological hypertrophy are fundamentally different. Further, they suggest that miR-222 may hold promise as a therapeutic target in pathological cardiac hypertrophy and heart failure.

The human heart can increase its size to supply more blood to the body’s organs. This process, called hypertrophy, can happen during exercise or be caused by medical conditions, such as high blood pressure or inherited genetic diseases. If hypertrophy is continually driven by illness, this can cause the heart to fail and no longer be able to properly pump blood around the body. For hypertrophy to happen, several molecular changes occur in the cells responsible for contracting the heart, including activation of the p38 pathway. Within this pathway is a p38 enzyme as well as a series of other proteins which are sequentially turned on in response to stress, such as inflammatory molecules or mechanical forces that alter the cell’s shape. There are different types of p38 enzyme which have been linked to other diseases, making them a promising target for drug development. However, clinical trials blocking individual members of the p38 family have had disappointing results. An alternative approach is to target other proteins involved in the p38 pathway, such as MKK6, but it is not known what effect this might have. To investigate, Romero-Becerra et al. genetically modified mice to not have any MKK6 protein. As a result, these mice had a shorter lifespan, with hypertrophy developing at a young age that led to heart problems. Romero-Becerra et al. used different mice models to understand why this happened, showing that a lack of MKK6 reduces the activity of a specific member of the p38 family called p38α. However, this blockage boosted a different branch of the pathway which involved two other p38 proteins, p38γ and p38δ. This, in turn, triggered another key pathway called mTOR which also promotes hypertrophy of the heart. These results suggest that drugs blocking MKK6 and p38α could lead to side effects that cause further harm to the heart. A more promising approach for treating hypertrophic heart conditions could be to inhibit p38γ and/or p38δ. However, before this can be fully explored, further work is needed to generate compounds that specifically target these proteins.

Therapeutic inhibition of PHF21B attenuates pathological cardiac hypertrophy by inhibiting the BMP4/GSK3β/β-catenin axis.

Targeting miR-30d reverses pathological cardiac hypertrophy.

Background: Physiological cardiac hypertrophy occurs commonly in response to exercise and can protect against pathological stress. In contrast, pathological hypertrophy occurs in disease and often precedes heart failure . Although physiological and pathological hypertrophy often involve distinct signaling mechanisms, miR-222 is an exercise-induced microRNA that is required for physiological hypertrophy but is also induced in pathological hypertrophy. Here, we sought to define the role of miR-222 in pathological hypertrophy. Methods and Results: We generated miR-222 gain-of-function (GOF) models through cardiac-specific constitutive transgenic miR-222 expression (TgC-miR-222) or somatic expression with AAV9-miR-222. Loss-of-function (LOF) was achieved using a locked nucleic antimiR (LNA) specific for miR-222. miR-222 GOF and LOF models manifested normal cardiac structure and function at baseline. After transverse aortic constriction (TAC), TgC-miR-222 had less pathological hypertrophy as well as better cardiac function (FS = 37.9% vs 28.7%, p<0.01) and survival (median survival = 120 days vs 54 days, p<0.05). Similarly, AAV9-miR-222 gene transfer immediately after TAC also better preserved cardiac function. Conversely, LNA-anti-miR-222 dramatically exacerbated pathological hypertrophy, cardiac dysfunction, and heart failure (FS = 24.4% vs 35.3%, p<0.01) after TAC. PUMA, a pro-apoptotic Bcl-2 family member and two transcription factors, Hmbox1 and NFATc3, were identified as novel, direct miR-222 targets contributing to its roles in this context. Conclusions: Although miR-222 is upregulated in both physiological and pathological hypertrophy, its roles in these conditions are quite different. In response to pressure overload, miR-222 inhibits pathological hypertrophy, adverse remodeling, and cardiac dysfunction. These findings reinforce the conceptual model that physiological and pathological hypertrophy are qualitatively distinct, rather than differing only in degree. Further, they suggest that miR-222 may hold promise as a potential therapeutic target in pathological cardiac hypertrophy and heart failure.

Comparative proteomic analysis of mouse models of pathological and physiological cardiac hypertrophy, with selection of biomarkers of pathological hypertrophy by integrative proteogenomics

During the past decade, advances in sequencing and genomics technology have transformed our understanding of the genome. Unexpectedly, these studies revealed that noncoding RNAs account for the vast majority of the transcribed genome, spurring intense interest in determining the functions of these molecules. Noncoding RNAs are a diverse family of transcripts that can be classified by size: RNAs <200 nucleotides are designated as small noncoding RNAs, which includes microRNAs (miRNA) and small interfering RNAs; RNAs >200 nucleotides are referred to as long noncoding RNAs (lncRNAs). miRNAs function as posttranscriptional repressors of gene expression that directly bind to target messenger RNAs to inhibit translation or induce transcript degradation. miRNAs play essential roles in cardiovascular physiology and pathophysiology, and clinical trials using promising miRNA targets in heart failure have recently commenced. Far less is currently known about lncRNAs, which are a more heterogeneous class of RNAs that participate in diverse cellular processes including transcriptional regulation, nuclear domain organization, and direct regulation of proteins or RNA molecules. Recently, lncRNAs have emerged as additional key players in cardiovascular health and disease, gaining attention both as potential therapeutic targets and biomarkers for a broad range of diseases.