Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 1181 2023-05-02 08:44:33 |
2 format correct Meta information modification 1181 2023-05-04 04:19:15 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Schenkl, C.; Heyne, E.; Doenst, T.; Schulze, P.C.; Nguyen, T.D. Strategies Targeting Mitochondrial Metabolism to Improve Cardiac Function. Encyclopedia. Available online: https://encyclopedia.pub/entry/43669 (accessed on 21 June 2024).
Schenkl C, Heyne E, Doenst T, Schulze PC, Nguyen TD. Strategies Targeting Mitochondrial Metabolism to Improve Cardiac Function. Encyclopedia. Available at: https://encyclopedia.pub/entry/43669. Accessed June 21, 2024.
Schenkl, Christina, Estelle Heyne, Torsten Doenst, Paul Christian Schulze, Tien Dung Nguyen. "Strategies Targeting Mitochondrial Metabolism to Improve Cardiac Function" Encyclopedia, https://encyclopedia.pub/entry/43669 (accessed June 21, 2024).
Schenkl, C., Heyne, E., Doenst, T., Schulze, P.C., & Nguyen, T.D. (2023, May 02). Strategies Targeting Mitochondrial Metabolism to Improve Cardiac Function. In Encyclopedia. https://encyclopedia.pub/entry/43669
Schenkl, Christina, et al. "Strategies Targeting Mitochondrial Metabolism to Improve Cardiac Function." Encyclopedia. Web. 02 May, 2023.
Strategies Targeting Mitochondrial Metabolism to Improve Cardiac Function
Edit

Heart failure (HF) is a condition in which heart function is insufficient to meet the body’s oxygen demand. It is not a specific cardiac disorder but rather a clinical syndrome characterized by increased intracardiac pressure and/ or reduced cardiac output resulting from diverse cardiac abnormalities. Therefore, HF may be the common end stage of numerous cardiovascular diseases, such as coronary artery disease, hypertension, cardiomyopathies, heart valve disease or a combination of these.

mitochondria metabolism heart failure oxidation cardiac function contractile dysfunction

1. Stimulation of Fatty Acid Oxidation

Over the last thirty years, there has been extensive research on using metabolic treatments to treat heart diseases, with a particular focus on cardiac FA utilization. However, there is no agreement on how myocardial FA oxidation should be modified in HF. While some researchers have suggested inhibiting FA oxidation as a potential metabolic strategy for treating heart failure (HF) [1][2], there is an increasing body of evidence that challenges this viewpoint. Studies on rodent models of pressure overload, myocardial infarction or genetic cardiomyopathy have shown protective effects associated with high-fat diets [3]. Additionally, stimulating myocardial FA oxidation has been found to preserve cardiac function in pressure overload [4][5] or myocardial infarction [6]. Because the transport of most fatty acids into the mitochondria matrix is dependent on L-carnitine, stimulating L-carnitine is crucial for the maintenance of FA oxidation. In a hypertensive rat model of HFpEF, L-carnitine supplementation reduced ventricular fibrosis, prevented pulmonary congestion and improved survival [7]. In addition to stimulating uptake and oxidation of fatty acids, L-carnitine may also increase glucose oxidation by stimulating pyruvate dehydrogenase in conditions of high levels of free FAs [8]. In research and meta-analysis, researchers found that approaches that promote cardiac FA oxidation significantly improve heart function while those that lower FA oxidation showed no effects [9].

2. Stimulation of Glucose Oxidation

Pathological hypertrophy has been associated with a redirection of glucose towards biosynthetic and regulatory pathways [10], which may limit the ability of glucose oxidation to compensate for the reduction in FA oxidation. To improve cardiac energetics, it may, therefore, be beneficial to stimulate glucose oxidation through the PDH complex. The most investigated PDH stimulator is dichloroacetate (DCA). DCA treatment reduced ventricular hypertrophy and improved cardiac function and survival in Dahl salt-sensitive rats with hypertension [11]. The observed effects were associated with enhanced flux through the pentose phosphate pathways, increased energy reserves and less oxidative damage and apoptosis [11]. DCA also improved postischemic cardiac output in hypertrophied rats [12]. Researchers' meta-analysis revealed that approaches increasing cardiac glucose oxidation significantly enhance ventricular function, while those inhibiting glucose oxidation are detrimental [9]. While there is compelling preclinical evidence supporting the advantages of improving myocardial glucose oxidation, the clinical significance of this metabolic approach is yet to be determined. Data on short-term effects of DCA in HF patients are inconsistent [13][14] and long-term data are lacking, possibly because of the risk of peripheral neuropathy in chronic treatment [15]. There is a need for novel drugs that target myocardial glucose oxidation. In a previous study, researchers found that treatment with glucagon-like peptide-1 (GLP-1) improved diastolic function and increased survival rates in a rat model of HFpEF. Notably, these effects were accompanied by a preservation of cardiac glucose oxidation. Researchers' findings not only imply that GLP-1 may boost glucose oxidation in the failing myocardium but also suggest enhancing cardiac glucose oxidation for HFpEF [16].

3. Stimulation of Ketone Body Oxidation

Ketone bodies may serve as additional or alternative substrates for the heart. In HF, increased myocardial utilization of ketone bodies has been consistently observed [17][18][19]. Since inhibition of ketone body oxidation in pressure-overloaded mouse hearts aggravated ventricular dysfunction [20][21], this change most likely represents a necessary metabolic adaptation to maintain ATP production. In keeping with this notion, ventricular remodeling and dysfunction in mice subjected to transverse aortic constriction and in canines with pacing-induced cardiomyopathy were ameliorated by feeding with a ketogenic diet [21]. It is noteworthy that sodium–glucose cotransporter-2 (SGLT2) inhibitors, which have been established as potent drugs for treating both HFrEF and HFpEF, are also associated with increased ketone body utilization. While ketone bodies may enhance the energy status of the failing heart by acting as alternative substrates, potential mechanisms underlying their cardioprotective effects have been discovered. For instance, in a mouse model of HFpEF, raising β-hydroxybutyrate levels reduced the formation of NLPR3 inflammasomes, mitochondrial hyperacetylation and dysfunction, as well as myocardial fibrosis [22]. Considering the effects of ketone bodies on multiple pathways, including histone deacetylation and redox signaling [23][24], additional mechanisms are likely but remain to be evaluated in the context of HF.

4. Modulation of Anaplerotic Pathways

As illustrated above, the TCA cycle pool is depleted, potentially resulting from an increased recruitment of amino acids for hypertrophic growth. Restoring the activity of the TCA cycle can be achieved by supplementing anaplerotic substrates. Inhibition of BCAA catabolism, which generates acetyl CoA and propionyl CoA, occurs in the failing heart [25]. Although activation of BCAA catabolism has been associated with reduced oxidative stress [25] and inflammation [26], the enrichment of the TCA cycle with acetyl CoA and propionyl CoA may also contribute to its therapeutic effects. Both acetyl CoA and propionyl CoA can be supplied by odd-chain ketone bodies. Researchers previously showed that feeding rats triheptanoin, which provides C5-ketone bodies to the heart, resulted in increased cardiac glucose oxidation and reduced ventricular hypertrophy and diastolic dysfunction following aortic constriction [27]. Similarly, supplementation of alpha-ketoglutarate in mice with aortic constriction ameliorated left ventricular hypertrophy, fibrosis and systolic dysfunction [28].
Another method to maintain cardiac anaplerotic activity is to provide the heart with exogenous amino acids. At first glance, this concept seems to contradict the benefits of activating BCAA catabolism. Nevertheless, if the downregulation of amino acid catabolism in the failing heart reflects its higher demand for amino acids, providing exogenous amino acids may prevent this maladaptation and retain anaplerosis. In line with this hypothesis, cardioprotection following amino acid supplementation has been reported in rats [29] and patients [30][31][32] with HF.

5. Targeting Mitochondrial Biogenesis, Morphology and Dynamics

Because PGC-1α signaling, which governs mitochondrial biogenesis and FA utilization, is downregulated in HF, activation of this pathway has been considered a promising approach to protect mitochondrial and heart function. However, studies have failed to demonstrate functional benefits of overexpressing PGC-1α in mice with aortic constriction [33][34]. Interestingly, overexpression of TFAM, a downstream signal of PGC-1α, reduced LV remodeling and preserved cardiac function in mice with myocardial infarction [35]. TFAM may protect mtDNA and mitigate Ca2+ mishandling and excessive ROS production. The import of exogenous TFAM with the help of TFAM-packed exosomes might represent one feasible way to improve mitochondrial biogenesis and function in HF [36].
Other interventions target mitochondrial morphology and dynamics. Pharmacologic inhibition of poly(ADP-ribose) polymerase (PARP) prevented mitochondrial fragmentation, increased mitochondria size and cristae density and prevented left ventricular hypertrophy in spontaneous hypertensive rats [37]. Efforts to restore mitochondrial phospholipid content by administration of exogenous cardiolipin were successful in cells [38]. However, similar attempts failed in a knock-down mouse model mimicking Barth syndrome with cardiomyopathy [38]. In mice with pressure overload-induced HF, treatment with the mitochondrial division inhibitor (Mdivi) decreased ventricular fibrosis and preserved cardiac function [39]. Finally, treatment with berberine activated mitophagy via the PINK1/Parkin pathway and preserved ventricular function in mice subjected to pressure overload [40].

References

  1. Karwi, Q.G.; Uddin, G.M.; Ho, K.L.; Lopaschuk, G.D. Loss of Metabolic Flexibility in the Failing Heart. Front. Cardiovasc. Med. 2018, 5, 68.
  2. Lopaschuk, G.D.; Karwi, Q.G.; Tian, R.; Wende, A.R.; Abel, E.D. Cardiac Energy Metabolism in Heart Failure. Circ. Res. 2021, 128, 1487–1513.
  3. Stanley, W.C.; Dabkowski, E.R.; Ribeiro, R.F., Jr.; O’Connell, K.A. Dietary fat and heart failure: Moving from lipotoxicity to lipoprotection. Circ. Res. 2012, 110, 764–776.
  4. Kolwicz, S.C., Jr.; Olson, D.P.; Marney, L.C.; Garcia-Menendez, L.; Synovec, R.E.; Tian, R. Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ. Res. 2012, 111, 728–738.
  5. Kaimoto, S.; Hoshino, A.; Ariyoshi, M.; Okawa, Y.; Tateishi, S.; Ono, K.; Uchihashi, M.; Fukai, K.; Iwai-Kanai, E.; Matoba, S. Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure. Am. J. Physiol. Heart Circ. Physiol. 2017, 312, H305–H313.
  6. Matsumura, N.; Takahara, S.; Maayah, Z.H.; Parajuli, N.; Byrne, N.J.; Shoieb, S.M.; Soltys, C.M.; Beker, D.L.; Masson, G.; El-Kadi, A.O.S.; et al. Resveratrol improves cardiac function and exercise performance in MI-induced heart failure through the inhibition of cardiotoxic HETE metabolites. J. Mol. Cell. Cardiol. 2018, 125, 162–173.
  7. Omori, Y.; Ohtani, T.; Sakata, Y.; Mano, T.; Takeda, Y.; Tamaki, S.; Tsukamoto, Y.; Kamimura, D.; Aizawa, Y.; Miwa, T.; et al. L-Carnitine prevents the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease. J. Hypertens. 2012, 30, 1834–1844.
  8. Calvani, M.; Reda, E.; Arrigoni-Martelli, E. Regulation by carnitine of myocardial fatty acid and carbohydrate metabolism under normal and pathological conditions. Basic Res. Cardiol. 2000, 95, 75–83.
  9. Nguyen, T.D.; Schenkl, C.; Schlattmann, P.; Heyne, E.; Doenst, T.; Schulze, P.C. Identifying metabolic treatment strategies for heart failure—A meta-analytic approach. Eur. Heart J. 2019, 40, 966.
  10. Nguyen, T.D.; Schulze, P.C. Lipid in the midst of metabolic remodeling—Therapeutic implications for the failing heart. Adv. Drug. Deliv. Rev. 2020, 159, 120–132.
  11. Kato, T.; Niizuma, S.; Inuzuka, Y.; Kawashima, T.; Okuda, J.; Tamaki, Y.; Iwanaga, Y.; Narazaki, M.; Matsuda, T.; Soga, T.; et al. Analysis of Metabolic Remodeling in Compensated Left Ventricular Hypertrophy and Heart Failure. Circ. Heart Fail. 2010, 3, 420–430.
  12. Wambolt, R.B.; Lopaschuk, G.D.; Brownsey, R.W.; Allard, M.F. Dichloroacetate improves postischemic function of hypertrophied rat hearts. J. Am. Coll. Cardiol. 2000, 36, 1378–1385.
  13. Bersin, R.M.; Wolfe, C.; Kwasman, M.; Lau, D.; Klinski, C.; Tanaka, K.; Khorrami, P.; Henderson, G.N.; de Marco, T.; Chatterjee, K. Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J. Am. Coll. Cardiol. 1994, 23, 1617–1624.
  14. Lewis, J.F.; DaCosta, M.; Wargowich, T.; Stacpoole, P. Effects of dichloroacetate in patients with congestive heart failure. Clin. Cardiol. 1998, 21, 888–892.
  15. Pfeffer, G.; Majamaa, K.; Turnbull, D.M.; Thorburn, D.; Chinnery, P.F. Treatment for mitochondrial disorders. Cochrane Database Syst. Rev. 2012, 2012, CD004426.
  16. Nguyen, T.D.; Shingu, Y.; Amorim, P.A.; Schenkl, C.; Schwarzer, M.; Doenst, T. GLP-1 Improves Diastolic Function and Survival in Heart Failure with Preserved Ejection Fraction. J. Cardiovasc. Transl. Res. 2018, 11, 259–267.
  17. Lommi, J.; Kupari, M.; Koskinen, P.; Naveri, H.; Leinonen, H.; Pulkki, K.; Harkonen, M. Blood ketone bodies in congestive heart failure. J. Am. Coll. Cardiol. 1996, 28, 665–672.
  18. Bedi, K.C., Jr.; Snyder, N.W.; Brandimarto, J.; Aziz, M.; Mesaros, C.; Worth, A.J.; Wang, L.L.; Javaheri, A.; Blair, I.A.; Margulies, K.B.; et al. Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure. Circulation 2016, 133, 706–716.
  19. Aubert, G.; Martin, O.J.; Horton, J.L.; Lai, L.; Vega, R.B.; Leone, T.C.; Koves, T.; Gardell, S.J.; Kruger, M.; Hoppel, C.L.; et al. The Failing Heart Relies on Ketone Bodies as a Fuel. Circulation 2016, 133, 698–705.
  20. Schugar, R.C.; Moll, A.R.; Andre d’Avignon, D.; Weinheimer, C.J.; Kovacs, A.; Crawford, P.A. Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling. Mol. Metab. 2014, 3, 754–769.
  21. Horton, J.L.; Davidson, M.T.; Kurishima, C.; Vega, R.B.; Powers, J.C.; Matsuura, T.R.; Petucci, C.; Lewandowski, E.D.; Crawford, P.A.; Muoio, D.M.; et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight 2019, 4, e124079.
  22. Deng, Y.; Xie, M.; Li, Q.; Xu, X.; Ou, W.; Zhang, Y.; Xiao, H.; Yu, H.; Zheng, Y.; Liang, Y.; et al. Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF. Circ. Res. 2021, 128, 232–245.
  23. Shimazu, T.; Hirschey, M.D.; Newman, J.; He, W.; Shirakawa, K.; Le Moan, N.; Grueter, C.A.; Lim, H.; Saunders, L.R.; Stevens, R.D.; et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 2013, 339, 211–214.
  24. Puchalska, P.; Crawford, P.A. Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics. Cell Metab. 2017, 25, 262–284.
  25. Sun, H.; Olson, K.C.; Gao, C.; Prosdocimo, D.A.; Zhou, M.; Wang, Z.; Jeyaraj, D.; Youn, J.-Y.; Ren, S.; Liu, Y.; et al. Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 2016, 133, 2038–2049.
  26. Wang, W.; Zhang, F.; Xia, Y.; Zhao, S.; Yan, W.; Wang, H.; Lee, Y.; Li, C.; Zhang, L.; Lian, K.; et al. Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction. 2016, 311, H1160–H1169.
  27. Nguyen, T.D.; Shingu, Y.; Amorim, P.A.; Schwarzer, M.; Doenst, T. Triheptanoin Alleviates Ventricular Hypertrophy and Improves Myocardial Glucose Oxidation in Rats With Pressure Overload. J. Card. Fail. 2015, 21, 906–915.
  28. An, D.; Zeng, Q.; Zhang, P.; Ma, Z.; Zhang, H.; Liu, Z.; Li, J.; Ren, H.; Xu, D. Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice. Redox Biol. 2021, 46, 102088.
  29. Tanada, Y.; Shioi, T.; Kato, T.; Kawamoto, A.; Okuda, J.; Kimura, T. Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats. Life Sci. 2015, 137, 20–27.
  30. Aquilani, R.; Viglio, S.; Iadarola, P.; Opasich, C.; Testa, A.; Dioguardi, F.S.; Pasini, E. Oral amino acid supplements improve exercise capacities in elderly patients with chronic heart failure. Am. J. Cardiol. 2008, 101, 104E–110E.
  31. Lombardi, C.; Carubelli, V.; Lazzarini, V.; Vizzardi, E.; Quinzani, F.; Guidetti, F.; Rovetta, R.; Nodari, S.; Gheorghiade, M.; Metra, M. Effects of oral amino Acid supplements on functional capacity in patients with chronic heart failure. Clin. Med. Insights Cardiol. 2014, 8, 39–44.
  32. Nichols, S.; McGregor, G.; Al-Mohammad, A.; Ali, A.N.; Tew, G.; O’Doherty, A.F. The effect of protein and essential amino acid supplementation on muscle strength and performance in patients with chronic heart failure: A systematic review. Eur. J. Nutr. 2020, 59, 1785–1801.
  33. Pereira, R.O.; Wende, A.R.; Crum, A.; Hunter, D.; Olsen, C.D.; Rawlings, T.; Riehle, C.; Ward, W.F.; Abel, E.D. Maintaining PGC-1α expression following pressure overload-induced cardiac hypertrophy preserves angiogenesis but not contractile or mitochondrial function. FASEB J. 2014, 28, 3691–3702.
  34. Karamanlidis, G.; Garcia-Menendez, L.; Kolwicz, S.C., Jr.; Lee, C.F.; Tian, R. Promoting PGC-1alpha-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts. Am. J. Physiol. Heart Circ. Physiol. 2014, 307, H1307–H1316.
  35. Ikeuchi, M.; Matsusaka, H.; Kang, D.; Matsushima, S.; Ide, T.; Kubota, T.; Fujiwara, T.; Hamasaki, N.; Takeshita, A.; Sunagawa, K.; et al. Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction. Circulation 2005, 112, 683–690.
  36. Kunkel, G.H.; Chaturvedi, P.; Tyagi, S.C. Mitochondrial pathways to cardiac recovery: TFAM. Heart Fail. Rev. 2016, 21, 499–517.
  37. Ordog, K.; Horvath, O.; Eros, K.; Bruszt, K.; Toth, S.; Kovacs, D.; Kalman, N.; Radnai, B.; Deres, L.; Gallyas, F., Jr.; et al. Mitochondrial protective effects of PARP-inhibition in hypertension-induced myocardial remodeling and in stressed cardiomyocytes. Life Sci. 2021, 268, 118936.
  38. Ikon, N.; Su, B.; Hsu, F.-F.; Forte, T.M.; Ryan, R.O. Exogenous cardiolipin localizes to mitochondria and prevents TAZ knockdown-induced apoptosis in myeloid progenitor cells. Biochem. Biophys. Res. Commun. 2015, 464, 580–585.
  39. Givvimani, S.; Munjal, C.; Tyagi, N.; Sen, U.; Metreveli, N.; Tyagi, S.C. Mitochondrial division/mitophagy inhibitor (Mdivi) ameliorates pressure overload induced heart failure. PLoS ONE 2012, 7, e32388.
  40. Abudureyimu, M.; Yu, W.; Cao, R.Y.; Zhang, Y.; Liu, H.; Zheng, H. Berberine Promotes Cardiac Function by Upregulating PINK1/Parkin-Mediated Mitophagy in Heart Failure. Front. Physiol. 2020, 11, 565751.
More
Information
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , , ,
View Times: 356
Revisions: 2 times (View History)
Update Date: 04 May 2023
1000/1000
Video Production Service