Hypertension and hypercholesterolemia are major cardiac risk factors that occur at a higher incidence with increased age. The activation of stress-associated signalling pathways within the heart, includes a family of mitogen activated protein kinase; specifically, c-jun N-terminal kinase (JNK) has been implicated during episodes of cardiac stress. Elevation of total JNK occurs in chronic stress and elevation of activated JNK takes place during acute stress. In this study, using JNK as a biomarker of cardiac stress we investigated the expression of total JNK and activated JNK in patients over 55 years of age, diagnosed with hypertension, hypercholesterolemia, and those receiving pharmacological treatment.
Our study examined right atrial appendage tissue from patients in sinus rhythm and >55 years post-surgery; coronary artery bypass or aortic valve replacement (n=27). Tissue was analysed by western blot for protein expression levels of total JNK (bands at 54 and 56 kDa.) and activated phosphorylated JNK (p-JNK at 46 kDa). Primary antibodies were from Cell Technologies, U.K. and secondary HRP antibodies from Dako, Denmark. Desmin (Abcam, U.K.) was used as a housekeeper to normalise for equal protein loading. Protein expression data were analysed based on clinical patient diagnosis and their current medication. Data are mean ± SEM, and statistical significance was determined by Student’s t-test if p<0.05. Ethical approval was granted by the University of Hull and NHS-REC.
Regardless of surgical procedure, patients showed no significant difference in right atrial total JNK nor p-JNK protein expression. However, patients diagnosed with hypertension possessed 72 ± 18% more total JNK protein compared with those who were normotensive (n=17 vs. n=10; p=0.003). Similarly, those patients with hypercholesterolemia possessed 67 ± 19% more total JNK protein than those within U.K. recommend guidelines of total cholesterol (n=9 vs. n=18; p=0.0045). Interestingly, no significant difference in total JNK protein expression were found in patients treated with statins, β-blockers, aspirin, calcium channel blockers or ACE-inhibiters.
When activation of JNK was investigated, p-JNK showed no significant difference in expression due to hypertension nor hypercholesterolemia. Also, those patients treated with a calcium channel blocker or aspirin showed no difference in p-JNK expression. Interestingly, p-JNK was significantly elevated in patients treated with statins, β-blockers and ACE-inhibitors (208 ± 37% statin vs. 100 ± 34% none; n=22 vs. n=5; p=0.025) (218 ± 43% β-blockers vs. 100 ± 13% none; n=17 vs. n=10; p=0.008) (231 ± 50% ACE-inhibitors vs. 100 ± 13% none; n=13 vs. n=14; p=0.011).
We conclude that elevated total JNK protein expression, indicative of chronic stress, was observed in aged patients with hypertension or hypercholesterolemia, whereas raised activated phosphorylated JNK indicates acute stress in patients treated pharmacologically with statins, β-blockers or ACE-inhibitors.
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