Cocaine Increases Mortality and Cardiac Mass in a Murine Transgenic Model of Acquired Immune Deficiency Syndrome

Sutliff, Roy L.; Haase, Chad P; Russ, Rodney; Hoit, Brian D.; Morris, Randal E.; Norman, Andrew B.; Lewis, William

doi:10.1097/01.lab.0000075555.93242.f2

Cited by 8 publications

(7 citation statements)

References 26 publications

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“…Here, addressing question two, weekly ECG recordings during the course of cocaine treatment showed a cumulative, dose-dependent prolongation of QT, but no change in heart rate, in mice that did not receive CocH vector. That outcome is consistent with another report that 10 days of 40-mg/kg cocaine dosing caused no heart rate fluctuations (Sutliff et al, 2003). Interestingly, that treatment failed to induce QT prolongation.…”

Section: Discussionsupporting

confidence: 82%

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

Murthy

Reyes

Geng

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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Cocaine addiction is associated with devastating medical consequences, including cardiotoxicity and risk-conferring prolongation of the QT interval. Viral gene transfer of cocaine hydrolase engineered from butyrylcholinesterase offers therapeutic promise for treatment-seeking drug users. Although previous preclinical studies have demonstrated benefits of this strategy without signs of toxicity, the specific cardiac safety and efficacy of engineered butyrylcholinesterase viral delivery remains unknown. Here, telemetric recording of electrocardiograms from awake, unrestrained mice receiving a course of moderately large cocaine doses (30 mg/kg, twice daily for 3 weeks) revealed protection against a 2-fold prolongation of the QT interval conferred by pretreatment with cocaine hydrolase vector. By itself, this prophylactic treatment did not affect QT interval duration or cardiac structure, demonstrating that viral delivery of cocaine hydrolase has no intrinsic cardiac toxicity and, on the contrary, actively protects against cocaine-induced QT prolongation.

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Section: Discussionsupporting

confidence: 82%

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

Murthy

Reyes

Geng

et al. 2016

The Journal of Pharmacology and Experimental Therapeutics

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“…To apply a metric to the microscopic observations, myocyte damage was assessed by blinded reviewers from multiple high-power field views of histology sections for each cohort. 30 The amount of myocytolysis was scored semiquantitatively on a scale from zero (no myocyte damage) to 4 þ (410 damaged myocytes) at high-power views. Average scores for each cohort are presented (Table 1).…”

Section: Cardiac Aconitase Activity In Tgs and Wtsmentioning

confidence: 99%

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

Kohler

Cucoranu

Fields

et al. 2009

Laboratory Investigation

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Transgenic mice (TG) were used to define mitochondrial oxidative stress and cardiomyopathy (CM) induced by zidovudine (AZT), an antiretroviral used to treat HIV/AIDS. Genetically engineered mice either depleted or overexpressed mitochondrial superoxide dismutase (SOD2 þ /À KOs and SOD2-OX, respectively) or expressed mitochondrially targeted catalase (mCAT). TGs and wild-type (WT) littermates were treated (oral AZT, 35 days). Cardiac mitochondrial H 2 O 2 , aconitase activity, histology and ultrastructure were analyzed. Left ventricle (LV) mass and LV end-diastolic dimension were determined echocardiographically. AZT induced cardiac oxidative stress and LV dysfunction in WTs. Cardiac mitochondrial H 2 O 2 increased and aconitase was inactivated in SOD2 þ /À KOs, and cardiac dysfunction was worsened by AZT. Conversely, the cardiac function in SOD2-OX and mCAT hearts was protected. In SOD2-OX and mCAT TG hearts, mitochondrial H 2 O 2 , LV mass and LV cavity volume resembled corresponding values from vehicle-treated WTs. AZT worsens cardiac dysfunction and increases mitochondrial H 2 O 2 in SOD2 þ /À KO. Conversely, both SOD2-OX and mCAT TGs prevent or attenuate AZT-induced cardiac oxidative stress and LV dysfunction. As dysfunctional changes are ameliorated by decreasing and worsened by increasing H 2 O 2 abundance, oxidative stress from H 2 O 2 is crucial pathogenetically in AZT-induced mitochondrial CM.

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“…M-mode echocardiogram studies were performed as described. 21 M-mode measurements of end-diastolic dimension (EDD), end-systolic dimension (ESD), intraventricular wall septum thickness (IVS) and end-diastolic posterior wall thickness (PW) were made from original tracings. Calculated variables included the following: left ventricular fractional shortening (FS ϭ (EDD Ϫ ESD)/EDD), relative wall thickness (RWT ϭ (IVSϩPW)/EDD), LV mass ϭ 1.06 ϫ ((EDD ϩ PW ϩ IVS) 3 Ϫ (EDD) 3 , and LV mass normalized by body weight (LV/BW).…”

Section: Echocardiographymentioning

confidence: 99%

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Xiao

Fuchs

Campbell

et al. 2004

The American Journal of Pathology

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191

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To investigate the local effects of angiotensin II on the heart, we created a mouse model with 100-fold normal cardiac angiotensin-converting enzyme (ACE), but no ACE expression in kidney or vascular endothelium. This was achieved by placing the endogenous ACE gene under the control of the ␣-myosin heavy chain promoter using targeted homologous recombination. These mice, called ACE 8/8, have cardiac angiotensin II levels that are 4.3-fold those of wild-type mice. Despite near normal blood pressure and a normal renal function, ACE 8/8 mice have a high incidence of sudden death. Both histological analysis and in vivo catheterization of the heart showed normal ventricular size and function. In contrast, both the left and right atria were three times normal size. ECG analysis showed atrial fibrillation and cardiac block. In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death. The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. A critical component of this system is angiotensin-converting enzyme (ACE), which produces the eight amino acid peptide angiotensin II, the effector molecule of the RAS. 1 ACE is a zinc metallopeptidase located on the cell surface of endothelium. In this location, ACE produces angiotensin II adjacent to vascular smooth muscle, a critical target organ for this vasoconstrictor. ACE is also produced by a variety of other tissues including renal tubular epithelium, activated macrophages, proximal gut epithelium, and areas of the brain. Endothelium and these other tissues make the isozyme of ACE, termed somatic ACE, which consists of two catalytic domains that are independently capable of producing angiotensin II. Studies of knockout mice established that somatic ACE influences blood pressure and other cardiovascular functions. 2,3 In contrast, within the testis, developing male germ cells produce a different ACE isozyme called testis ACE, which plays an important role in normal male reproduction. 4 In addition to regulating normal physiology, substantial evidence suggests that the RAS plays an important role in disease, including heart disease. 5 Genetic studies reported a link between somatic ACE polymorphisms and the incidence of cardiac hypertrophy, sudden cardiac death, and acute coronary events. 6 This is consistent with the clinical effectiveness of ACE inhibitors in treating heart failure. 7 The beneficial effects of ACE inhibitors may not be solely the result of blood pressure reduction since other antihypertensive drugs do not produce the same effect. Rather, ACE may directly influence heart function through the local production of angiotensin II. Studies have found that angiotensinogen, renin, and ACE exist in the heart, implying that local generation of angiotensin II

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Cocaine Increases Mortality and Cardiac Mass in a Murine Transgenic Model of Acquired Immune Deficiency Syndrome

Cited by 8 publications

References 26 publications

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

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