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      Murine Models of Heart Failure With Preserved Ejection Fraction : A “Fishing Expedition”

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          Heart failure with preserved ejection fraction (HFpEF) is characterized by signs and symptoms of heart failure in the presence of a normal left ventricular ejection fraction. Despite accounting for up to 50% of all clinical presentations of heart failure, the mechanisms implicated in HFpEF are poorly understood, thus precluding effective therapy. The pathophysiological heterogeneity in the HFpEF phenotype also contributes to this disease and likely to the absence of evidence-based therapies. Limited access to human samples and imperfect animal models that completely recapitulate the human HFpEF phenotype have impeded our understanding of the mechanistic underpinnings that exist in this disease. Aging and comorbidities such as atrial fibrillation, hypertension, diabetes and obesity, pulmonary hypertension, and renal dysfunction are highly associated with HFpEF, yet the relationship and contribution between them remains ill-defined. This review discusses some of the distinctive clinical features of HFpEF in association with these comorbidities and highlights the advantages and disadvantage of commonly used murine models used to study the HFpEF phenotype.

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          Effects of the obese gene product on body weight regulation in ob/ob mice.

          C57BL/6J mice with a mutation in the obese (ob) gene are obese, diabetic, and exhibit reduced activity, metabolism, and body temperature. Daily intraperitoneal injection of these mice with recombinant OB protein lowered their body weight, percent body fat, food intake, and serum concentrations of glucose and insulin. In addition, metabolic rate, body temperature, and activity levels were increased by this treatment. None of these parameters was altered beyond the level observed in lean controls, suggesting that the OB protein normalized the metabolic status of the ob/ob mice. Lean animals injected with OB protein maintained a smaller weight loss throughout the 28-day study and showed no changes in any of the metabolic parameters. These data suggest that the OB protein regulates body weight and fat deposition through effects on metabolism and appetite.
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            Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice.

             X Weng,  R Tepper,  G Duyk (1996)
            OB-R is a high affinity receptor for leptin, an important circulating signal for the regulation of body weight. We identified an alternatively spliced transcript that encodes a form of mouse OB-R with a long intracellular domain. db/db mice also produce this alternatively spliced transcript, but with a 106 nt insertion that prematurely terminates the intracellular domain. We further identified G --> T point mutation in the genomic OB-R sequence in db/db mice. This mutation generates a donor splice site that converts the 106 nt region to a novel exon retained in the OB-R transcript. We predict that the long intracellular domain form of OB-R is crucial for initiating intracellular signal transduction, and as a corollary, the inability to produce this form of OB-R leads to the severe obese phenotype found in db/db mice.
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              Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease.


                Author and article information

                JACC Basic Transl Sci
                JACC Basic Transl Sci
                JACC: Basic to Translational Science
                25 December 2017
                December 2017
                25 December 2017
                : 2
                : 6
                : 770-789
                [a ]Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
                [b ]Evans Department of Internal Medicine, Boston University School of Medicine, Boston, Massachusetts
                [c ]Cardiovascular Section, Boston University School of Medicine, Boston, Massachusetts
                Author notes
                [] Address for correspondence: Dr. Flora Sam, Whitaker Cardiovascular Institute, Cardiovascular Medicine Section, Boston University School of Medicine, 700 Albany Street, W507, Boston, Massachusetts 02118. flora.sam@ 123456bmc.org
                © 2017 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                STATE-OF-THE-ART REVIEW


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