Age-associated changes in cardiac structure and function, together with estrogen loss, contribute to the progression of heart failure with preserved ejection fraction in older women. To investigate the effects of aging and estrogen loss on the development of its precursor, asymptomatic left ventricular diastolic dysfunction, echocardiograms were performed in 10 middle-aged (20 months) and 30 old-aged (30 months) female Fischer344×Brown-Norway rats, 4 and 8 weeks after ovariectomy (OVX) and sham procedures (gonads left intact). The cardioprotective potential of administering chronic G1, the selective agonist to the new G-protein-coupled estrogen receptor (GPER), was further evaluated in old rats (Old-OVX+G1) versus age-matched, vehicle-treated OVX and gonadal intact rats. Advanced age and estrogen loss led to decreases in myocardial relaxation and elevations in filling pressure, in part, due to reductions in phosphorylated phospholamban and increases in cardiac collagen deposition. Eight weeks of G-protein-coupled estrogen receptor activation in Old-OVX+G1 rats reversed the adverse effects of age and estrogen loss on myocardial relaxation through increases in sarcoplasmic reticulum Ca ATPase expression and reductions in interstitial fibrosis. These findings may explain the preponderance of heart failure with preserved ejection fraction in older postmenopausal women and provide a promising, late-life therapeutic target to reverse or halt the progression of left ventricular diastolic dysfunction.

Rationale Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling that leads to pulmonary congestion, uncompensated right-ventricle (RV) failure, and premature death. Preclinical studies have demonstrated that the G protein-coupled estrogen receptor (GPER) is cardioprotective in male rats and that its activation elicits vascular relaxation in rats of either sex. Objectives To study the effects of GPER on the cardiopulmonary system by the administration of its selective agonist G1 in male rats with monocrotaline (MCT)-induced PH. Methods Rats received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Experimental groups were as follows: control, MCT + vehicle, and MCT + G1 (400 μg/kg/day subcutaneous). Animals (n = 5 per group) were treated with vehicle or G1 for 14 days after disease onset. Measurements and main results Activation of GPER attenuated exercise intolerance and reduced RV overload in PH rats. Rats with PH exhibited echocardiographic alterations, such as reduced pulmonary flow, RV hypertrophy, and left-ventricle dysfunction, by the end of protocol. G1 treatment reversed these PH-related abnormalities of cardiopulmonary function and structure, in part by promoting pulmonary endothelial nitric oxide synthesis, Ca2+ handling regulation and reduction of inflammation in cardiomyocytes, and a decrease of collagen deposition by acting in pulmonary and cardiac fibroblasts. Conclusions G1 was effective to reverse PH-induced RV dysfunction and exercise intolerance in male rats, a finding that have important implications for ongoing clinical evaluation of new cardioprotective and vasodilator drugs for the treatment of the disease.

IntroductionPulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats.MethodsAn in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). In the in vivo experiments, PH was induced in male Wistar rats by a single intraperitoneal injection of 60 mg/kg MCT. Rats were divided into the following groups: control (saline injection only), MCT + vehicle, MCT + sildenafil, MCT + LASSBio 1359 and MCT + combination of sildenafil and LASSBio 1359. Fourteen days after the MCT injection, rats were treated daily with oral administration of the regimen therapies or vehicle for 14 days. Cardiopulmonary system function and structure were evaluated by echocardiography. RV systolic pressure and PA endothelial function were measured.ResultsIsobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat PAs. Combined therapy with sildenafil and LASSBio 1359 but not monotreatment with low dosages of either sildenafil or LASSBio 1359 ameliorated all of PH related abnormalities in cardiopulmonary function and structure in MCT challenged rats.ConclusionsThe combination of sildenafil and LASSBio 1359 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to improve quality of life and outcomes for PH patients.

Introduction: Pulmonary hypertension (PH) is primarily a disease of women (female-to-male ratio 4:1) and is associated with cardiac dysfunction. Aim: The activation of GPER by its agonist G1 was evaluated in monocrotaline (MCT)-induced PH rats. Methods: Depletion of estrogen was induced by bilateral oophorectomy (OVX; n = 18) in female Wistar rats (12 wks old). Experimental groups were: SHAM or OVX that received i.p. injection of MCT (60 mg/kg) for PH induction followed by administration of vehicle or G1 (400 μg/kg/day s.c.) for 14 days (n=7 per group). Hemodynamic parameters were determined by echocardiography. The effects of G1 in the maintenance of exercise capacity was investigated using a treadmill test. Results: MCT injection and estrogen loss led to a significant decrease in pulmonary acceleration time (PAT) and an increase in RV free wall thickness and MCT-related changes were attenuated by treatment with G1 ( P < 0.05; Table 1). Right ventricular systolic pressure (RVSP) was higher in MCT-injected rats and the magnitude of this increase in OVX group was significantly higher than that in SHAM group. G1 normalized RVSP in both SHAM and OVX rats (Table 1). G1 treatment reversed altered expression of SERCA2a and phospholamban proteins in the RV (Table 1). Interaction between estrogen loss and MCT also reduced treadmill time to exhaustion in PH rats ( P < 0.05), and chronic administration of G1 restored the exercise capacity ( P < 0.05). Conclusion: G1 reversed PH-related cardiopulmonary dysfunction and exercise intolerance in female rats, a finding that may have important implications for the ongoing clinical evaluation of new drugs for the treatment of the disease in aging females.

Objectives: Investigate the effects of LASSBio-1773, a ligand of PPAR-gamma receptor with hypoglycemic activity, in a model of diabetic cardiomyopathy (DC) induced by streptozotocin (STZ). Methods: Male Wistar rats received a single i.v. injection of STZ (60 mg/kg) for diabetes induction. Experimental groups were: control, STZ + vehicle, and STZ + LASSBio-1773 (50 mg/kg/day i.p.). Animals were treated with vehicle or LASSBio-1773 for 7 days after disease onset. Cardiovascular function and plasma biochemistry evaluations were performed by the end of protocol. Findings: Serum glucose, total cholesterol and triglycerides levels were significantly higher in STZ group, and treatment with LASSBio-1773 normalized both hyperglycemia and hypertriglyceridemia (Table 1). Following 8 weeks of STZ injection, echocardiography showed that left ventricular (LV) filling pressures (E/e′) increased in STZ + vehicle group. Treatment with LASSBio-1773 improved diastolic parameters in STZ-injected rats but no changes were observed on LV ejection fraction (Table 1). STZ + vehicle group have developed hypertension which was reduced after treatment with LASSBio-1773 (Table 1). Vascular dysfunction was found by the reduced acetylcholine maximum relaxation (Ach-MR) in isolated aortic rings from STZ + vehicle group which was improved with LASSBio-1773 administration. Conclusions: LASSBio-1773 improved cardiovascular function and lipid profile of diabetic rats, indicating that this novel PPAR-gamma agonist is a promising candidate for the treatment of diabetes-related cardiac complications.