Domenick A. Prosdocimo

Case Western Reserve University

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Mukesh K. Jain

Case Western Reserve University

Mukesh K. Jain

Brown University

Rongli Zhang

Chinese Academy of Medical Sciences & Peking Union Medical College

Daiana Weiss

Emory University

Michelle Puchowicz

Case Western Reserve University

Ashruth Reddy

Children's Healthcare of Atlanta

Xudong Liao

Nankai University

M. Neale Weitzmann

Emory University

Qianjin Li

Emory University

Xinyang Zhao

University of Alabama at Birmingham

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Case Western Reserve University

113

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Harvard University

University Hospitals Case Medical Center

University Hospitals of Cleveland

Brigham and Women's Hospital

Massachusetts General Hospital

University of California, Los Angeles

Medizinische Hochschule Hannover

Cornell University

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KLF15 Establishes the Landscape of Diurnal Expression in the Heart

Cell Reports (2015)

Lilei Zhang Domenick A. Prosdocimo Xiaodong Bai Fu Chen Rongli Zhang

Highlights•KLF15 directly regulates metabolic genes in the active phase•KLF15 is required for repression of oscillation by REV-ERBα and NCORSummaryCircadian rhythms offer temporal control of anticipatory physiologic adaptations in animals. In the mammalian cardiovascular system, the importance of these rhythms is underscored by increased cardiovascular disease in shift workers, findings recapitulated in experimental animal models. However, a nodal regulator that allows integration of central and peripheral information and coordinates cardiac rhythmic output has been elusive. Here, we show that kruppel-like factor 15 (KLF15) governs a biphasic transcriptomic oscillation in the heart with a maximum ATP production phase and a remodeling and repair phase corresponding to the active and resting phase of a rodent. Depletion of KLF15 in cardiomyocytes leads to a disorganized oscillatory behavior without phasic partition despite an intact core clock. Thus, KLF15 is a nodal connection between the clock and meaningful rhythmicity in the heart.Graphical abstract

10.1016/j.celrep.2015.11.038

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Citations (77)

Kruppel-like factor 15 is critical for vascular inflammation

Journal of Clinical Investigation (2013)

Yuan Lu Lisheng Zhang Xudong Liao Panjamaporn Sangwung Domenick A. Prosdocimo

Activation of cells intrinsic to the vessel wall is central to the initiation and progression of vascular inflammation. As the dominant cellular constituent of the vessel wall, vascular smooth muscle cells (VSMCs) and their functions are critical determinants of vascular disease. While factors that regulate VSMC proliferation and migration have been identified, the endogenous regulators of VSMC proinflammatory activation remain incompletely defined. The Kruppel-like family of transcription factors (KLFs) are important regulators of inflammation. In this study, we identified Kruppel-like factor 15 (KLF15) as an essential regulator of VSMC proinflammatory activation. KLF15 levels were markedly reduced in human atherosclerotic tissues. Mice with systemic and smooth muscle-specific deficiency of KLF15 exhibited an aggressive inflammatory vasculopathy in two distinct models of vascular disease: orthotopic carotid artery transplantation and diet-induced atherosclerosis. We demonstrated that KLF15 alters the acetylation status and activity of the proinflammatory factor NF-κB through direct interaction with the histone acetyltransferase p300. These studies identify a previously unrecognized KLF15-dependent pathway that regulates VSMC proinflammatory activation.

Proinflammatory cytokine

10.1172/jci68552

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Citations (79)

Abstract 357: Branched-Chain Amino Acid Metabolic Reprogramming in Heart Failure

Circulation Research (2013)

Haipeng Sun Kristine C. Olson Meiyi Zhou Domenick A. Prosdocimo Gao Chen

Metabolic remodeling is an integral part of heart failure. Current studies are largely focusing on glucose and fatty acid metabolism, while little is known about the changes in amino acid homeostasis during heart failing process. Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, serve as not only essential building blocks for protein synthesis, but also important energy source and signaling molecules that have significant effects on cell growth and function. In this study, we demonstrated that the BCAA catabolic intermediate branched-chain keto acid (BCKA) accumulated in both mouse and human failing heart. BCAA catabolic genes were selectively and significantly down-regulated at both mRNA and protein levels in failing heart in mice, mimicking a similar expression pattern observed in neonatal heart. Using both in vitro and in vivo models, we established that BCAA catabolic genes were regulated by Krüppel-like factor 15 (KLF15), a key transcriptional regulator for glucose, fat, and amino acid nutrient homeostasis, suggesting that the KLF15-mediated BCAA catabolic regulation is part of the metabolic remodeling during heart failure. Genetic ablation of PP2Cm, a key regulator of BCAA catabolism, led to a significant impairment of BCAA catabolic activities and accumulation of BCKA in cardiac tissue. Importantly, PP2Cm deficiency accelerated heart failure under pressure overload. PP2Cm deficiency or elevated BCKA induced oxidative stress in cardiomyocytes and impairment of oxygen consumption and ATP production of mitochondria. Antioxidant treatment ameliorated the heart failure progression in PP2Cm deficient animals. Taken together, our data established for the first time that BCAA catabolic reprogramming is an integral component of metabolic remodeling during heart failure, and this remodeling can significantly contribute to heart failure progression.

Catabolism

Branched-chain amino acid

Homeostasis

Energy homeostasis

10.1161/res.113.suppl_1.a357

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Impact of anaerobic glycolysis and oxidative substrate selection on contractile function and mechanical efficiency during moderate severity ischemia

AJP Heart and Circulatory Physiology (2008)

Lufang Zhou Hazel Huang Tracy A McElfresh Domenick A. Prosdocimo William C. Stanley

The role of anaerobic glycolysis and oxidative substrate selection on contractile function and mechanical efficiency during moderate severity myocardial ischemia is unclear. We hypothesize that 1) preventing anaerobic glycolysis worsens contractile function and mechanical efficiency and 2) increasing glycolysis and glucose oxidation while inhibiting free fatty acid oxidation improves contractile function during ischemia. Experiments were performed in anesthetized pigs, with regional ischemia induced by a 60% decrease in left anterior descending coronary artery blood flow for 40 min. Three groups were studied: 1) no treatment, 2) inhibition of glycolysis with iodoacetate (IAA), or 3) hyperinsulinemia and hyperglycemia (HI + HG). Glucose and free fatty acid oxidation were measured using radioisotopes and anaerobic glycolysis from net lactate efflux and myocardial lactate content. Regional contractile power was assessed from left ventricular pressure and segment length in the anterior wall. We found that preventing anaerobic glycolysis with IAA during ischemia in the absence of alterations in free fatty acid and glucose oxidation did not adversely affect contractile function or mechanical efficiency during myocardial ischemia, suggesting that anaerobic glycolysis is not essential for maintaining residual contractile function. Increasing glycolysis and glucose oxidation with HI + HG inhibited free fatty acid oxidation and improved contractile function and mechanical efficiency. In conclusion, these results show a dissociation between myocardial function and anaerobic glycolysis during moderate severity ischemia in vivo, suggesting that metabolic therapies should not be aimed at inhibiting anaerobic glycolysis per se, but rather activating insulin signaling and/or enhancing carbohydrate oxidation and/or decreasing fatty acid oxidation.

Anaerobic glycolysis

Carbohydrate Metabolism

10.1152/ajpheart.00561.2008

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Loss of Ptpmt1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice

eLife (2023)

Hong Zheng Qianjin Li Shanhu Li Zhiguo Li Marco Brotto

While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here, we report that the deletion of Ptpmt1 , a mitochondria-based phosphatase, critically alters mitochondrial fuel selection – the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced. Ptpmt1 knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly, Ptpmt1 deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that Ptpmt1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources.

Muscle Atrophy

Knockout mouse

Bioenergetics

10.7554/elife.86944.3

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KLF15 and PPARαCooperate to Regulate Cardiomyocyte Lipid Gene Expression and Oxidation

PPAR Research (2015)

Domenick A. Prosdocimo Jenine E. John Lilei Zhang Elizabeth S Efraim Rongli Zhang

The metabolic myocardium is an omnivore and utilizes various carbon substrates to meet its energetic demand. While the adult heart preferentially consumes fatty acids (FAs) over carbohydrates, myocardial fuel plasticity is essential for organismal survival. This metabolic plasticity governing fuel utilization is under robust transcriptional control and studies over the past decade have illuminated members of the nuclear receptor family of factors (e.g., PPARα) as important regulators of myocardial lipid metabolism. However, given the complexity of myocardial metabolism in health and disease, it is likely that other molecular pathways are likely operative and elucidation of such pathways may provide the foundation for novel therapeutic approaches. We previously demonstrated that Kruppel-like factor 15 (KLF15) is an independent regulator of cardiac lipid metabolism thus raising the possibility that KLF15 and PPARα operate in a coordinated fashion to regulate myocardial gene expression requisite for lipid oxidation. In the current study, we show that KLF15 binds to, cooperates with, and is required for the induction of canonical PPARα-mediated gene expression and lipid oxidation in cardiomyocytes. As such, this study establishes a molecular module involving KLF15 and PPARα and provides fundamental insights into the molecular regulation of cardiac lipid metabolism.

10.1155/2015/201625

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Citations (53)

Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis

Journal of Clinical Investigation (2015)

Xudong Liao Rongli Zhang Yuan Lu Domenick A. Prosdocimo Panjamaporn Sangwung

Mitochondrial homeostasis is critical for tissue health, and mitochondrial dysfunction contributes to numerous diseases, including heart failure. Here, we have shown that the transcription factor Kruppel-like factor 4 (KLF4) governs mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Adult mice with cardiac-specific Klf4 deficiency developed cardiac dysfunction with aging or in response to pressure overload that was characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial shape, size, ultrastructure, and alignment. Evaluation of mitochondria isolated from KLF4-deficient hearts revealed a reduced respiration rate that is likely due to defects in electron transport chain complex I. Further, cardiac-specific, embryonic Klf4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. We determined that KLF4 binds to, cooperates with, and is requisite for optimal function of the estrogen-related receptor/PPARγ coactivator 1 (ERR/PGC-1) transcriptional regulatory module on metabolic and mitochondrial targets. Finally, we found that KLF4 regulates autophagy flux through transcriptional regulation of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis.

KLF4

DNAJA3

10.1172/jci79964

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Citations (115)

BMPing Up Angiogenesis via BMPER

Arteriosclerosis Thrombosis and Vascular Biology (2011)

Domenick A. Prosdocimo Mukesh K. Jain

10.1161/atvbaha.111.233890

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Citations (6)

Loss of PTPMT1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Hong Zheng Qianjin Li Shanhu Li Zhiguo Li Marco Brotto

ABSTRACT While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here we report that the deletion of PTPMT1, a mitochondria-based phosphatase, critically alters mitochondrial fuel selection – the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced. PTPMT1 knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly, PTPMT1 deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that PTPMT1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources.

Muscle Atrophy

Knockout mouse

10.1101/2023.01.09.523031

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Autocrine ATP release coupled to extracellular pyrophosphate accumulation in vascular smooth muscle cells

AJP Cell Physiology (2009)

Domenick A. Prosdocimo Dezmond C. Douglas Andrea Romani W. Charles O’Neill George Dubyak

Extracellular inorganic pyrophosphate (PP i ) is a potent suppressor of physiological calcification in bone and pathological calcification in blood vessels. Ectonucleotide pyrophosphatase/phosphodiesterases (eNPPs) generate PP i via the hydrolysis of ATP released into extracellular compartments by poorly understood mechanisms. Here we report that cultured vascular smooth muscle cells (VSMC) from rat aorta generate extracellular PP i via an autocrine mechanism that involves ATP release tightly coupled to eNPP activity. The nucleotide analog β,γ-methylene ATP (MeATP or AMPPCP) was used to selectively suppress ATP metabolism by eNPPs but not the CD39-type ecto-ATPases. In the absence of MeATP, VSMC generated extracellular PP i to accumulate ≥600 nM within 2 h while steadily maintaining extracellular ATP at 1 nM. Conversely, the presence of MeATP completely suppressed PP i accumulation while increasing ATP accumulation. Probenecid, which inhibits PP i efflux dependent on ANK, a putative PP i transporter or transport regulator, reduced extracellular PP i accumulation by approximately twofold. This indicates that autocrine ATP release coupled to eNPP activity comprises ≥50% of the extracellular PP i -generating capacity of VSMC. The accumulation of extracellular PP i and ATP was markedly attenuated by reduced temperature but was insensitive to brefeldin A, which suppresses constitutive exocytosis of Golgi-derived secretory vesicles. The magnitude of extracellular PP i accumulation in VSMC cultures increased with time postplating, suggesting that ATP release coupled to PP i generation is upregulated as cultured VSMC undergo contact-inhibition of proliferation or deposit extracellular matrix.

10.1152/ajpcell.00619.2008

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Citations (56)