Role of Pyruvate Kinase M2 (PKM2) in Cardiovascular Diseases

Rihan, Mohd; Sharma, Shyam Sunder

doi:10.1007/s12265-022-10321-1

Cited by 13 publications

(5 citation statements)

References 136 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We identified Pkm2 among the interacting proteins of Jmjd4, which is a pyruvate kinase normally absent or expressed at low levels in adult cardiomyocytes. 11 The enzymatic activity of Pkm2 is much lower than Pkm1, which is abundantly expressed in adult cardiomyocytes. 13 Given the accumulation of metabolites upstream of pyruvate upon Jmjd4 loss-of-function, this interaction is particularly interesting and is consistent with our metabolic dysfunctional phenotype (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…9 PKM1 is present in cardiomyocytes and other terminally differentiated tissues with high energy demand, and PKM2 is present in tissues with anabolic functions, proliferating cells, and cancer cells. 10,11 PKM1 has constitutively high catalytic activity, whereas PKM2 enzyme activity is subject to complex allosteric regulation, 12 which allows cells to switch between glycolysis and biosynthesis. 11 Pkm2 was recently found to promote proliferation of cardiomyocytes, 13 but it is still unknown whether it plays a role in DCM and what regulates Pkm2 expression and activity in cardiomyocytes.…”

mentioning

confidence: 99%

“…10,11 PKM1 has constitutively high catalytic activity, whereas PKM2 enzyme activity is subject to complex allosteric regulation, 12 which allows cells to switch between glycolysis and biosynthesis. 11 Pkm2 was recently found to promote proliferation of cardiomyocytes, 13 but it is still unknown whether it plays a role in DCM and what regulates Pkm2 expression and activity in cardiomyocytes.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Tang

Feng

et al. 2023

Circulation

View full text Add to dashboard Cite

BACKGROUND: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. METHODS: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. RESULTS: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. CONCLUSION: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Tang

Feng

et al. 2023

Circulation

View full text Add to dashboard Cite

show abstract

“…In vitro, PKM2 expression did not upregulation during the hypertrophy of NRVMs, which contradicts the data observed in vivo. We believe that this inconsistency could be attributed to the naturally higher expression levels of PKM2 in fetal hearts [53] . NRVMs we utilized were derived from fetal rats, which is a commonly used cell type for cardiac research [54] .…”

Section: Discussionmentioning

confidence: 96%

M-type pyruvate kinase 2 (PKM2) tetramerization alleviates the progression of right ventricle failure by regulating oxidative stress and mitochondrial dynamics

Guo,

Wang,

Qin

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: Right ventricle failure (RVF) is a progressive heart disease that has yet to be fully understood at the molecular level. Elevated M-type pyruvate kinase 2 (PKM2) tetramerization alleviates heart failure, but detailed molecular mechanisms remain unclear. Objective: We observed changes in PKM2 tetramerization levels during the progression of right heart failure and in vitro cardiomyocyte hypertrophy and explored the causal relationship between altered PKM2 tetramerization and the imbalance of redox homeostasis in cardiomyocytes, as well as its underlying mechanisms. Ultimately, our goal was to propose rational intervention strategies for the treatment of RVF. Method: We established RVF in Sprague Dawley (SD) rats by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right heart function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. TEPP-46 was used both in vivo and in vitro to promote PKM2 tetramerization. Results: We observed that oxidative stress and mitochondrial disorganization were associated with increased apoptosis in the right ventricular tissue of RVF rats. Quantitative proteomics revealed that PKM2 was upregulated during RVF and negatively correlated with the cardiac function. Facilitating PKM2 tetramerization promoted mitochondrial network formation and alleviated oxidative stress and apoptosis during cardiomyocyte hypertrophy. Moreover, enhancing PKM2 tetramer formation improved cardiac mitochondrial morphology, mitigated oxidative stress and alleviated heart failure. Conculsion: Disruption of PKM2 tetramerization contributed to RVF by inducing mitochondrial fragmentation, accumulating ROS, and finally promoted the progression of cardiomyocyte apoptosis. Facilitating PKM2 tetramerization holds potential as a promising therapeutic approach for RVF.

show abstract

“…Researchers are continuously exploring novel targets and agents that can reduce the burden of CVDs. Marine-derived drugs are emerging therapeutics in the recent era [ 179 , 180 ]. Experiments and investigations have indicated several marine natural products that are effective for CVDs with minimum adverse effects.…”

Section: Future Prospectusmentioning

confidence: 99%

Marine-Derived Compounds Applied in Cardiovascular Diseases: Submerged Medicinal Industry

et al. 2023

Self Cite

View full text Add to dashboard Cite

Cardiovascular diseases (CVDs) are among the most impactful illnesses globally. Currently, the available therapeutic option has several side effects, including hypotension, bradycardia, arrhythmia, and alteration in different ion concentrations. Recently, bioactive compounds from natural sources, including plants, microorganisms, and marine creatures, have gained a lot of interest. Marine sources serve as reservoirs for new bioactive metabolites with various pharmacological activities. The marine-derived compound such as omega-3 acid ethyl esters, xyloketal B, asperlin, and saringosterol showed promising results in several CVDs. The present review focuses on marine-derived compounds’ cardioprotective potential for hypertension, ischemic heart disease, myocardial infarction, and atherosclerosis. In addition to therapeutic alternatives, the current use of marine-derived components, the future trajectory, and restrictions are also reviewed.

show abstract

Role of Pyruvate Kinase M2 (PKM2) in Cardiovascular Diseases

Cited by 13 publications

References 136 publications

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

M-type pyruvate kinase 2 (PKM2) tetramerization alleviates the progression of right ventricle failure by regulating oxidative stress and mitochondrial dynamics

Marine-Derived Compounds Applied in Cardiovascular Diseases: Submerged Medicinal Industry

Contact Info

Product

Resources

About