Shiraj Sen

Return to the fetal gene program

A hallmark of cardiac metabolism before birth is the predominance of carbohydrate use for energy provision. After birth, energy substrate metabolism rapidly switches to the oxidation of fatty acids. This switch accompanies the expression of “adult” isoforms of metabolic enzymes and other proteins. However, in a variety of pathophysiologic conditions, including hypoxia, ischemia, hypertrophy, atrophy, diabetes, and hypothyroidism, the postnatal heart returns to the “fetal” gene program. These adaptive mechanisms are also a feature of the failing heart muscle, where at a certain point this fetal‐like reprogramming no longer suffices to support cardiac structure and function. We advance the hypothesis that in the postnatal heart, metabolic remodeling triggers the process through glycosylation of transcription factors, potentially protecting the stressed heart from irreversible functional impairment and programmed cell death. In other words, we propose a metabolic link to gene expression in the heart.

Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

ABSTRACT Long-chain acyl coenzyme A (acyl-CoA) synthetase isoform 1 (ACSL1) catalyzes the synthesis of acyl-CoA from long-chain fatty acids and contributes the majority of cardiac long-chain acyl-CoA synthetase activity. To understand its functional role in the heart, we studied mice lacking ACSL1 globally (Acsl1T−/−) and mice lacking ACSL1 in heart ventricles (Acsl1H−/−) at different times. Compared to littermate controls, heart ventricular ACSL activity in Acsl1T−/− mice was reduced more than 90%, acyl-CoA content was 65% lower, and long-chain acyl-carnitine content was 80 to 90% lower. The rate of [14C]palmitate oxidation in both heart homogenate and mitochondria was 90% lower than in the controls, and the maximal rates of [14C]pyruvate and [14C]glucose oxidation were each 20% higher. The mitochondrial area was 54% greater than in the controls with twice as much mitochondrial DNA, and the mRNA abundance of Pgc1α and Errα increased by 100% and 41%, respectively. Compared to the controls, Acsl1T−/− and Acsl1H−/− hearts were hypertrophied, and the phosphorylation of S6 kinase, a target of mammalian target of rapamycin (mTOR) kinase, increased 5-fold. Our data suggest that ACSL1 is required to synthesize the acyl-CoAs that are oxidized by the heart, and that without ACSL1, diminished fatty acid (FA) oxidation and compensatory catabolism of glucose and amino acids lead to mTOR activation and cardiac hypertrophy without lipid accumulation or immediate cardiac dysfunction.

Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart.

Background Changes in energy substrate metabolism are first responders to hemodynamic stress in the heart. We have previously shown that hexose‐6‐phosphate levels regulate mammalian target of rapamycin (mTOR) activation in response to insulin. We now tested the hypothesis that inotropic stimulation and increased afterload also regulate mTOR activation via glucose 6‐phosphate (G6P) accumulation. Methods and Results We subjected the working rat heart ex vivo to a high workload in the presence of different energy‐providing substrates including glucose, glucose analogues, and noncarbohydrate substrates. We observed an association between G6P accumulation, mTOR activation, endoplasmic reticulum (ER) stress, and impaired contractile function, all of which were prevented by pretreating animals with rapamycin (mTOR inhibition) or metformin (AMPK activation). The histone deacetylase inhibitor 4‐phenylbutyrate, which relieves ER stress, also improved contractile function. In contrast, adding the glucose analogue 2‐deoxy‐d‐glucose, which is phosphorylated but not further metabolized, to the perfusate resulted in mTOR activation and contractile dysfunction. Next we tested our hypothesis in vivo by transverse aortic constriction in mice. Using a micro‐PET system, we observed enhanced glucose tracer analog uptake and contractile dysfunction preceding dilatation of the left ventricle. In contrast, in hearts overexpressing SERCA2a, ER stress was reduced and contractile function was preserved with hypertrophy. Finally, we examined failing human hearts and found that mechanical unloading decreased G6P levels and ER stress markers. Conclusions We propose that glucose metabolic changes precede and regulate functional (and possibly also structural) remodeling of the heart. We implicate a critical role for G6P in load‐induced mTOR activation and ER stress.

Remodeling of Glucose Metabolism Precedes Pressure Overload -Induced Left Ventricular Hypertrophy: Review of a Hypothesis

When subjected to pressure overload, the ventricular myocardium shifts from fatty acids to glucose as its main source for energy provision and frequently increases its mass. Here, we review the evidence in support of the concept that metabolic remodeling, measured as an increased myocardial glucose uptake using dynamic positron emission tomography (PET) with the glucose analogue 2-deoxy-2-[18F]fluoro-D-glucose (FDG), precedes the onset of left ventricular hypertrophy (LVH) and heart failure. Consistent with this, early intervention with propranolol, which attenuates glucose uptake, prevents the maladaptive metabolic response and preserves cardiac function in vivo. We also review ex vivo studies suggesting a link between dysregulated myocardial glucose metabolism, intracellular accumulation of glucose 6-phosphate (G6P) and contractile dysfunction of the heart. G6P levels correlate with activation of mTOR (mechanistic target of rapamycin) and endoplasmic reticulum stress. This sequence of events could be prevented by pretreatment with rapamycin (mTOR inhibition) or metformin (enzyme 5′-AMP-activated protein kinase activation). In conclusion, we propose that metabolic imaging with FDG PET may provide a novel approach to guide the treatment of patients with hypertension-induced LVH.

Metabolic adaptation follows contractile dysfunction in the heart of obese Zucker rats fed a high-fat "Western" diet.

The normal heart responds to changes in its metabolic milieu by changing relative oxidation rates of energy‐providing substrates. We hypothesized that this flexibility is lost when genetically obese rats are fed a high‐caloric, high‐fat “Western” diet (WD). Male Zucker obese (ZO) and Zucker lean (ZL) rats were fed either control or WD composed of 10 kcal% and 45 kcal% fat, respectively, for 7 or 28 days. Cardiac triglycerides and mRNA transcript levels were measured in situ. Substrate oxidation rates and cardiac power were measured ex vivo. Hearts from ZO rats fed WD for 7 days showed decreased cardiac power and increased cardiac triglyceride content, but no change in oleate oxidation rates or mRNA transcript levels of pyruvate dehydrogenase kinase‐4 (PDK‐4), uncoupling protein‐3 (UCP‐3), and mitochondrial (MTE‐1) and cytosolic thioesterase‐1(CTE‐1). When fed WD for 28 days, ZO rats showed no further decrease in cardiac power and no further increase in intramyocardial triglyceride levels compared to ZO rats fed the same diet for 7 days only, but did show significantly increased oleate oxidation rates and transcript levels of CTE‐1, MTE‐1, PDK‐4, and UCP‐3. In contrast, hearts from ZL rats fed WD showed increased rates of oleate oxidation and increased transcript levels of the fatty acid responsive genes investigated, and no further deterioration of contractile function. We conclude that exposing a genetic model of obesity to the nutrient stress of WD results in an early reversible loss of metabolic flexibility of the heart that is accompanied by contractile dysfunction.

Bariatric surgery to unload the stressed heart: a metabolic hypothesis

Obesity is an independent risk factor for cardiovascular disease. Data from the Framingham Study have reported a higher incidence of heart failure in obese individuals compared with a normal cohort. The body initially copes with the abundance of fuel present in an obese milieu by storing it in adipose tissue. However, when the storage capacity is exceeded, the excess energy is taken up and stored ectopically as fat in vital organs such as the heart. Indeed, intramyocardial lipid overload is present in hearts of obese patients, as well as in hearts of animal models of obesity, and is associated with a distinct gene expression profile and cardiac dysfunction. By imposing a metabolic stress on the heart, obesity causes it to hypertrophy and ultimately to fail. Conventional measures to treat obesity include diet, exercise, and drugs. More recently, weight loss surgery (WLS) has achieved increasing prominence because of its ability to reduce the neurohumoral load, normalize metabolic dysregulation, and improve overall survival. The effects of WLS on systemic metabolic, neurohumoral, and hemodynamic parameters are well described and include an early normalization of serum glucose and insulin levels as well as reduction in blood pressure. WLS is also associated with reverse cardiac remodeling, regression of left ventricular hypertrophy, and improved left ventricular and right ventricular function. By targeting the source of the excess energy, we hypothesize that WLS improves contractile function by limiting exogenous substrate availability to the metabolically overloaded heart. These changes have also been found to be associated with increased levels of adiponectin and improved insulin sensitivity. Taken together, the sustained beneficial effects of WLS on left ventricular mass and function highlight the need to better understand the mechanism by which obesity regulates cardiovascular physiology.

Targeted Metabolic Imaging to Improve the Management of Heart Disease

Tracer techniques are powerful methods for assessing rates of biological processes in vivo. A case in point is intermediary metabolism of energy providing substrates, a central feature of every living cell. In the heart, the tight coupling between metabolism and contractile function offers an opportunity for the simultaneous assessment of cardiac performance at different levels in vivo: coronary flow, myocardial perfusion, oxygen delivery, metabolism, and contraction. Noninvasive imaging techniques used to identify the metabolic footprints of either normal or perturbed cardiac function are discussed.

Contents Vol. 130, 2015

E. Abadie, Saint Denis D.H. Adams, New York, N.Y. C.W. Akins, Boston, Mass. J.S. Alpert, Tucson, Ariz. E.A. Amsterdam, Davis, Calif. W.S. Aronow, Valhalla, N.Y. J.J. Badimon, New York, N.Y. J. Bax, Leiden R.C. Becker, Durham, N.C. G.A. Beller, Charlottesville, Va. P.C. Block, Atlanta, Ga. R.O. Bonow, Chicago, Ill. A.S. Budzikowski, Brooklyn, N.Y. A.J. Camm, London B.A. Carabello, Houston, Tex. K. Chatterjee, Iowa City, I.A. P.F. Cohn, Stony Brook, N.Y. J. Coromilas, New Brunswick, N.J. M.H. Crawford, San Francisco, Calif. J.E. Dalen, Tucson, Ariz. S. Dalla Volta, Padova P.C. Deedwania, Fresno, Calif. A.N. De Maria, San Diego, Calif. J.A. Eleft eriades, New Haven, Conn. U. Elkayam, Los Angeles, Calif. C. Erol, Ankara M.D. Ezekowitz, Wynnewood, Pa. R. Ferrari, Ferrara G. Filippatos, Athens G.I. Fishman, New York, N.Y. K. Fox, London G.S. Francis, Minneapolis, Minn. V. Fuster, New York, N.Y. B.J. Gersh, Rochester, Minn. W. Gersony, New York, N.Y. J.P. Gold, Toledo, Ohio R.J. Goldberg, Worcester, Mass. M.E. Goldman, New York, N.Y. P.J. Goldschmidt, Miami, Fla. J. Gore, Worcester, Mass. J.L. Halperin, New York, N.Y. Z.-X. He, Beijing D. Heistad, Iowa City, Iowa E.M. Herrold, Brooklyn, N.Y. G. Heusch, Essen C.A. Hochreiter, New York, N.Y.