AimsIn contrast to the membrane bound adenylyl cyclases, the soluble adenylyl cyclase (sAC) is activated by bicarbonate and divalent ions including calcium. sAC is located in the cytosol, nuclei and mitochondria of several tissues including cardiac muscle. However, its role in cardiac pathology is poorly understood. Here we investigate whether sAC is involved in hypertrophic growth using two different model systems.Methods and resultsIn isolated adult rat cardiomyocytes hypertrophy was induced by 24 h β1-adrenoceptor stimulation using isoprenaline (ISO) and a β2-adrenoceptor antagonist (ICI118,551). To monitor hypertrophy cell size along with RNA/DNA- and protein/DNA ratios as well as the expression level of α-skeletal actin were analyzed. sAC activity was suppressed either by treatment with its specific inhibitor KH7 or by knockdown. Both pharmacological inhibition and knockdown blunted hypertrophic growth and reduced expression levels of α-skeletal actin in ISO/ICI treated rat cardiomyocytes. To analyze the underlying cellular mechanism expression levels of phosphorylated CREB, B-Raf and Erk1/2 were examined by western blot. The results suggest the involvement of B-Raf, but not of Erk or CREB in the pro-hypertrophic action of sAC. In wild type and sAC knockout mice pressure overload was induced by transverse aortic constriction. Hemodynamics, heart weight and the expression level of the atrial natriuretic peptide were analyzed. In accordance, transverse aortic constriction failed to induce hypertrophy in sAC knockout mice. Mechanistic analysis revealed a potential role of Erk1/2 in TAC-induced hypertrophy.ConclusionSoluble adenylyl cyclase might be a new pivotal player in the cardiac hypertrophic response either to long-term β1-adrenoceptor stimulation or to pressure overload.

BackgroundToll-like receptors (TLRs) are involved in a variety of cardiovascular disorders, including septic cardiomyopathy, ischemia/reperfusion, heart failure, and cardiac hypertrophy. Previous research revealed that TLR4 promotes cardiac hypertrophy in vivo. Therefore, we investigated whether TLR2 is also involved in the development of cardiac hypertrophy.MethodsTlr2 deficient and wild type mice were subjected to transverse aortic constriction (TAC) or sham operation procedure. Left ventricular, heart and lung weights as well as hemodynamic parameters were determined after 3, 14 or 28 days. Real-time RT PCR was used to evaluate left ventricular gene expression. Protein content was determined via ELISA.ResultsTAC increased systolic left ventricular pressure, contraction and relaxations velocities as well as the heart weight in both genotypes. Tlr2 deficiency significantly enhanced cardiac hypertrophy after 14 and 28 days of TAC. Left ventricular end-diastolic pressure and heart rate increased in Tlr2−/− TAC mice only. Fourteen days of TAC led to a significant elevation of ANP, BNP, TGFβ and TLR4 mRNA levels in Tlr2−/− left ventricular tissue.ConclusionThese data suggest that Tlr2 deficiency may promote the development of cardiac hypertrophy and ventricular remodeling after transverse aortic constriction.

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Perinatal blockade of renin‐angiotensin system (RAS) has a long‐term antihypertensive effect in spontaneously‐hypertensive rats, whereas this treatment induces salt‐sensitive hypertension in adult normotensive strained rats. This study tests the hypothesis that inhibition of the RAS from conception to young mature life induces salt‐sensitive increased blood pressure via angiotensin II‐induced sympathetic overactivity in adult male rats. Female Sprague‐Dawley rats were fed normal rat chow and given water alone (Control) or water containing captopril (an angiotensin‐converting enzyme inhibitor, 400 mg/l; Captopril) from conception until weaning. After weaning, the male offspring drank water or water containing captopril until 5 weeks of age followed by normal rat chow and water alone for all rats until 7 weeks of age. Thereafter, they were given water alone (Control, Captopril) or 1% NaCl solution (Control+1%, Captopril+1%). At 9 weeks of age, all animals were implanted with femoral arterial and venous catheters. Forty‐eight hours later, blood samples were collected to measure non‐fasting blood glucose, hematocrit, and plasma sodium and potassium concentrations. Then arterial pressure and heart rate were continuously recorded and baroreflex sensitivity was determined by phenylephrine and sodium nitroprusside in freely moving conscious rats. After an overnight fasting, glucose tolerance tests were performed. All animals were then fed with a normal rat chow and captopril in drinking water for 2 days and the same experiments were repeated. Body weights, kidney weights, kidney to body weight ratios, heart to body weight ratios, fasting and non‐fasting blood sugar, glucose tolerance, and heart rates were not significantly different among groups, while plasma potassium levels significantly decreased in Control+1% and Captopril compared to Control groups. Further, resting mean arterial pressure significantly increased in Captopril+1% compared to other groups (Control 103.1 ± 2.1 mm Hg, Control+1% 97.6 ± 2.2 mm Hg, Captopril 100.6 ± 1.5 mm Hg, Captopril+1% 110.7 ± 1.4 mm Hg; p < 0.05). The increased mean arterial pressure of the Captopril+1% group is consistent to its sympathetic overactivity (estimated by arterial pressure variability), hypernatremia (Control 123.2 ± 0.0 mEq/l, Control+1% 124.0 ± 0.4 mEq/l, Captopril 124.6 ± 0.4 mEq/l, Captopril+1% 132.0 ± 0.6 mEq/l; p < 0.05), and blunted baroreflex sensitivity, compared to the other three groups. These differences were improved, at least in part, by two‐day oral captopril treatment. In addition, the arterial pressure differences were eliminated by either acute ganglionic blockade (hexamethonium) or acute central sympathetic inhibition (clonidine). The present study suggests that inhibition of the RAS in the early life induces RAS overactivity to cause salt‐sensitive increased blood pressure via sympathetic nerve stimulation and depressed baroreflex sensitivity in adult male rats.Support or Funding InformationThis work was supported by Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.