Fibronectin gene expression in aortic regurgitation: relative roles of mitogen-activated protein kinases.

OBJECTIVES: In aortic regurgitation (AR), fibronectin (FN) expression is upregulated. This study sought to determine signal transduction pathways involved in upregulation of FN expression in AR. METHODS: Cardiac fibroblasts (CF) from rabbits with surgically induced AR and matched controls (NL) were cultured and assayed for FN expression and kinase activity with and without inhibitors of kinases JNK, p38 mitogen-activated protein kinase (MAPK) and extracellular response kinase (ERK). NL CF also were subjected to cyclic strain mimicking AR for 24 h in culture with and without inhibitors. RESULTS: AR CF exhibited 2.9-fold greater c-Jun phosphorylation (p < 0.01) and 1.5- to 2-fold greater ATF2 phosphorylation (p < 0.05-0.01) than NL. JNK and p38MAPK inhibition reduced c-Jun and ATF2 phosphorylation to NL; ERK inhibition had no effect. FN mRNA expression was similar in pattern to kinase activities. Cyclic strain in NL CF increased c-Jun phosphorylation 2-fold versus unstrained controls (p < 0.005). This was suppressed by inhibition of JNK but not p38MAPK. CONCLUSION: FN expression in response to the acute mechanical strain resembling AR is upregulated primarily via JNK. However, in chronic AR both JNK and p38MAPK are involved. These signaling pathways represent potential therapeutic targets for normalizing extracellular matrix (ECM) composition and contractile force transmission, believed to be related to ECM composition/organization, in AR.

Use of baculovirus-expressed glycoprotein H in an enzyme-linked immunosorbent assay developed to assess exposure to chelonid fibropapillomatosis-associated herpesvirus and its relationship to the prevalence of fibropapillomatosis in sea turtles.

Chelonid fibropapillomatosis-associated herpesvirus (CFPHV) is an alphaherpesvirus believed to cause marine turtle fibropapillomatosis (FP). A serodiagnostic assay was developed for monitoring sea turtle populations for CFPHV exposure. CFPHV glycoprotein H (gH) expressed in recombinant baculovirus was used in an enzyme-linked immunosorbent assay (ELISA) to detect virus-specific 7S turtle antibodies. Using captive-reared green turtles (Chelonia mydas) with no history of virus exposure as "known negatives" and others with experimentally induced FP as "known positives," the assay had 100% specificity but low sensitivity, as seroconversion was detected in only half of the turtles bearing experimentally induced tumors. Antibodies were detected only in samples collected after cutaneous fibropapillomas appeared, consistent with observations that tumors are significant sites of virion production and antigen expression and the possibility that prolonged/repeated virus shedding may be required for adequate stimulation of 7S antibody responses to gH. Natural routes of infection, however, may produce higher seroconversion rates. High gH antibody seroprevalences ( approximately 80%) were found among wild green turtles in three Florida localities with different FP prevalences, including one site with no history of FP. In addition, all eight loggerhead turtles (Caretta caretta) tested were seropositive despite FP being uncommon in this species. The possibility that CFPHV infection may be common relative to disease suggests roles for environmental and host factors as modulators of disease expression. Alternatively, the possibility of other antigenically similar herpesviruses present in wild populations cannot be excluded, although antibody cross-reactivity with the lung/eye/trachea disease-associated herpesvirus was ruled out in this study.

Telmisartan ramipril combination therapy reduces strokes and improves cardiac and renal protection in stroke prone spontaneously hypertensive rats.

Clinical and animal experimental studies suggest that combination therapy using angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors provides superior blood pressure (BP) lowering and target organ protection than either agent alone. We tested combination therapy with telmisartan and ramipril in lowering BP and protecting against stroke and target-organ damage in salt-fed stroke prone spontaneously hypertensive rats. Twenty-five rats were assigned to each of five groups: control (C), telmisartan (T), ramipril (R), and telmisartan + ramipril at full (TR) and at half-dose ((1/2)TR). Full dose telmisartan was 1 mg/kg/day and ramipril .4 mg/kg/day. Rats were fed a stroke prone diet for 8 weeks starting at age 7.5 weeks. Eighty-three percent C and 56% R showed behavioral signs of stroke. There were no strokes in other groups. BP was lower than control in all groups and lowest in TR. Urinary protein excretion, renal damage scores, and left ventricle cardiac collagen areas were lower than controls in all telmisartan treatment groups and lowest in TR. Telmisartan was superior to ramipril in preventing strokes, and telmisartan/ramipril combination therapy provided better BP control and greater cardio-renal protection than telmisartan alone.