Erin Bruce

Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis

Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right‐heart failure and death. A dys‐regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non‐peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well‐established monocrotaline (MCT) rat model of PH.

17β-Estradiol modulates local cardiac renin-angiotensin system to prevent cardiac remodeling in the DOCA-salt model of hypertension in rats

Ventricular remodeling can play a detrimental role in the progression of cardiovascular diseases, leading to heart failure. The current study was designed to investigate the effects of 17beta-estradiol (E2) on cardiac remodeling. Cardiac fibrosis and hypertrophy were examined in deoxycorticosterone acetate (DOCA)-salt treated rats with chronic, six-week administration of two different doses of E2. Bilaterally ovariectomized (Ovex) female Sprague-Dawley rats were randomly assigned to one of the following groups: Ovex-control; Ovex-DOCA; Ovex-DOCA+low-dose E2 (1.66 microg/day); or Ovex-DOCA+high-dose E2 (2.38 microg/day). All DOCA-treated rats were uninephrectomized and drinking water was replaced by 0.15M NaCl solution for the remainder of the study period. DOCA-salt treatment resulted in a significant increase in blood pressure, which was not altered by estrogen replacement. Histological examinations revealed marked cardiac remodeling (both ventricular hypertrophy and interstitial fibrosis) with DOCA treatment, which was attenuated in animals receiving estrogen therapy. Western blot analysis demonstrated increased cardiac levels of angiotensin converting enzyme (ACE) with DOCA treatment, which was attenuated by E2 replacement. Furthermore, increased levels of cardiac angiotensin converting enzyme 2 (ACE2) protein were observed in animals receiving high-dose E2 replacement. These findings suggest that physiologically relevant estrogen replacement therapy has blood pressure-independent cardioprotective effects, which are possibly mediated through modulation of the cardiac renin-angiotensin system.

Therapeutic potential of adipose stem cell-derived conditioned medium against pulmonary hypertension and lung fibrosis.

Pulmonary hypertension (PH) and pulmonary fibrosis (PF) are life threatening cardiopulmonary diseases. Existing pharmacological interventions have failed to improve clinical outcomes or reduce disease‐associated mortality. Emerging evidence suggests that stem cells offer an effective treatment approach against various pathological conditions. It has been proposed that their beneficial actions may be mediated via secretion of paracrine factors. Herein, we evaluated the therapeutic potential of conditioned media (CM) from adipose stem cells (ASCs) against experimental models of PH and PF.

Onset of leptin resistance shows temporal differences related to dose or pulsed treatment

Leptin administration results in leptin resistance presenting a significant barrier to therapeutic use of leptin. Consequently, we examined two hypotheses. The first examined the relationship between leptin dose and development of physiological and biochemical signs of leptin resistance. We hypothesized lower doses of leptin would produce proportional reductions in body weight without the adverse leptin-induced leptin resistance. The second compared pulsed central leptin infusion to continuous leptin infusion. We hypothesized that pulsed infusion at specific times of the day would evoke favorable body weight reductions while tempering the development of leptin-induced leptin resistance. The first experiment examined leptin responsiveness, including food intake, body weight and hypothalamic STAT3 phosphorylation to increasing doses of viral gene delivery of leptin. Varying the dose proved inconsequential with respect to long-term therapy and demonstrated proportional development of leptin resistance. The second experiment examined leptin responsiveness to pulsed central leptin infusion, comparing pulsed versus constant infusion of 3μg/day leptin or a 2h morning versus a 2h evening pulsed leptin infusion. Pulsed delivery of the supramaximal dose of 3μg/day was not different than constant delivery. Morning pulsed infusion of the submaximal dose of 0.25μg reduces food intake only over subsequent immediate meal period and was associated with body weight reductions, but results in cellular leptin resistance. Evening pulsed infusion did not decrease food intake but reduces body weight and maintains full leptin signaling. The positive benefit for pulsed delivery remains speculative, yet potentially may provide an alternative mode of leptin therapy.

The intricacies of the renin-angiotensin-system in metabolic regulation.

Over recent years, the renin-angiotensin-system (RAS), which is best-known as an endocrine system with established roles in hydromineral balance and blood pressure control, has emerged as a fundamental regulator of many additional physiological and pathophysiological processes. In this manuscript, we celebrate and honor Randall Sakais commitment to his trainees, as well as his contribution to science. Scientifically, Randall made many notable contributions to the recognition of the RASs roles in brain and behavior. His interests, in this regard, ranged from its traditionally-accepted roles in hydromineral balance, to its less-appreciated functions in stress responses and energy metabolism. Here we review the current understanding of the role of the RAS in the regulation of metabolism. In particular, the opposing actions of the RAS within adipose tissue vs. its actions within the brain are discussed.

Anorexic response to rapamycin does not appear to involve a central mechanism.

The authors have previously demonstrated that a low and intermittent peripheral dose of rapamycin (1 mg/kg three times/week) to rats inhibited mTORC1 signalling, but avoided the hyperlipidemia and diabetes‐like syndrome associated with higher doses of rapamycin. The dosing regimen reduced food intake, body weight, adiposity, serum leptin and triglycerides. mTORC1 signalling was inhibited in both liver and hypothalamus, suggesting some of the actions, in particular the decrease in food intake, may be the results of a central mechanism. To test this hypothesis, rapamycin (30 μg/day for 4 weeks) was infused into 23–25‐month‐old F344xBN rats by intracerebroventricular (icv) mini pumps. Our results demonstrated that central infusion did not alter food intake or body weight, although there was a tendency for a decrease in body weight towards the end of the study. mTORC1 signalling, evidenced by decreased phosphorylation of S6 protein at end of 4 weeks, was not activated in liver, hypothalamus or hindbrain. Fat and lean mass, sum of white adipose tissues, brown adipose tissue, serum glucose, insulin and leptin levels remained unchanged. Thus, these data suggest that the anorexic and body weight responses evident with peripheral rapamycin are not the result of direct central action. The tendency for decreased body weight towards the end of study, suggests that there is either a slow transport of centrally administered rapamycin into the periphery, or that there is delayed action of rapamycin at sites in the brain.

Drugs, Exercise, and the Melanocortin-4 Receptor— Different Means, Same Ends: Treating Obesity

As the percentage of obese humans expands, new options for weight loss are being explored. Body weight homeostasis is the result of a balance between energy intake (food) and expenditure (activity). A shift in homeostasis into a negative balance results in weight loss. Two potential options available for the management of body weight, as related to the melanocortin system, are exercise (increase energy expenditure) and drugs targeting the melanocortin-4 receptors for satiety.

Coupling corticotropin-releasing-hormone and angiotensin converting enzyme 2 dampens stress responsiveness in male mice

ABSTRACT This study used mice to evaluate whether coupling expression of corticotropin‐releasing hormone (CRH) and angiotensin converting enzyme 2 (ACE2) creates central interactions that blunt endocrine and behavioral responses to psychogenic stress. Central administration of diminazene aceturate, an ACE2 activator, had no effect on restraint‐induced activation of the hypothalamic‐pituitary‐adrenal (HPA) axis; however, mice that ubiquitously overexpress ACE2 had reduced plasma corticosterone (CORT) and pituitary expression of POMC mRNA. The Cre‐LoxP system was used to restrict ACE2 overexpression to CRH synthesizing cells and probe whether HPA axis suppression was the result of central ACE2 and CRH interactions. Within the paraventricular nucleus of the hypothalamus (PVN), mice with ACE2 overexpression directed to CRH had a ≈2.5 fold increase in ACE2 mRNA, which co‐localized with CRH mRNA. Relative to controls, mice overexpressing ACE2 in CRH cells had a decreased CORT response to restraint as well as decreased CRH mRNA in the PVN and CEA and POMC mRNA in the pituitary. Administration of ACTH similarly increased plasma CORT, indicating that the blunted HPA axis activation that accompanies ACE2 overexpression in CRH cells is centrally mediated. Anxiety‐like behavior was assessed to determine whether the decreased HPA axis activation was predictive of anxiolysis. Mice with ACE2 overexpression directed to CRH cells displayed decreased anxiety‐like behavior in the elevated plus maze and open field when compared to that of controls. Collectively, these results suggest that exogenous ACE2 suppresses CRH synthesis, which alters the central processing of psychogenic stress, thereby blunting HPA axis activation and attenuating anxiety‐like behavior. HighlightsExogenous ACE2 is necessary for dampening stress‐evoked HPA axis activation.Overexpressing ACE2 in CRH cells attenuates stress‐induced HPA axis activation.Overexpressing ACE2 in CRH cells reduces anxiety‐like behavior.

ACE2 activator diminazene aceturate reduces adiposity but preserves lean mass in young and old rats

Abstract The obesity epidemic is multi‐generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme‐2 [ACE2]/angiotensin‐(1‐7)[Ang‐(1‐7)]/Mas receptor (MasR) axis in obese animal models leads to significant reductions in body weight. It was hypothesized that activation of ACE2 via diminazene aceturate (DIZE) will significantly reduce body weight of rats fed a high fat diet. Young and old (4 and 23 months, respectively) male Fisher 344 × Brown Norway rats were fed 60% high fat diet for one week, and subsequently given either 15 mg/kg/day DIZE s.c. or vehicle for three weeks. DIZE treatment resulted in a significant reduction of food intake and body weight in both young and old animals. However, that decrease was so dramatic in the older animals that they all nearly stopped eating. Interestingly, the TD‐NMR assessments revealed that the weight‐loss was primarily a result of decreased body fat percentage, with a relative preservation of lean mass. Tissue weights confirm the significant loss of white adipose tissue (WAT), with no change in muscle weights. Gene expression and serum ACE2 activity analyses implied that increased activation of the ACE2/Ang‐(1‐7)/MasR axis plays a role in reducing fat mass. Collectively, our results suggest that DIZE may be a useful tool in the study of obesity; however, caution is recommended when using this compound in older animals due to severe anorectic effects, although there is a mechanism by which muscle is preserved. HighlightsObesity is an epidemic in older individualsIncreasing angiotensin converting enyme‐2 (ACE2)via DIZE reduces body weight in rats fed a high fat dietYoung and old rats fed DIZE while on a HFD decreased fat and maintained muscle massOlder animals experienced a severe anorectic response to DIZEDIZE in older animals causes severe anorexia and weight loss;although there is a mechanism that preserves muscle mass.