Disertasi

Efek Doksisiklin terhadap Cardiac Remodeling pada Model Tikus Hipertensi Kronis dengan Uninefrektomi Diikuti Induksi Deoxycorticosterone Acetate dan Garam Fisiologis = Effect of Doxycycline on Cardiac Remodeling in Chronic Hypertension Rats with Uninephrectomy Followed by Induction Deoxycorticosterone Acetate and Physiological Salt.

Latar Belakang: Hipertensi mendorong terjadinya cardiac remodeling sebagai faktor risiko terjadinya heart failure preserved ejection fraction. Hingga saat ini terapi gagal jantung yang dipicu hipertensi kronik hanya didasari gejala klinik dan belum bisa menyembuhkan kondisi ini. Doksisiklin (DOXY) merupakan antibiotik spektrum luas dan memiliki aktivitas antioksidan. Tujuan penelitian ini untuk mendapatkan efek proteksi DOXY terhadap cardiac remodeling pada tikus hipertensi kronik dengan uninefrektomi diikuti induksi deoxycorticosterone acetate (DOCA) dan garam fisiologis serta kemungkinan mekanisme yang mendasarinya. Metode: Dua puluh lima ekor tikus jantan, Sprague-Dawley dibagi secara acak menjadi lima kelompok yaitu Normal, DOCA, DOCA+DOXY15, DOCA+DOXY30, dan DOCA+Irbesartan. Kelompok Normal menerima normal saline peroral, kelompok DOCA dilakukan uninefrektomi, diinjeksi DOCA 20 mg/kgBB subkutan, 2x/minggu dan 1% NaCl dalam air minum untuk menginduksi hipertensi kronik. DOXY diberikan dosis masing-masing 15mg/kgBB dan 30 mg/kgBB oral, IRB diberikan dosis 20mg/kgBB oral, pemberian selama 5 minggu. Tekanan darah dan ekokardiografi diperiksa. Serum darah dikumpulkan untuk pemeriksaan biomarker jantung. Sampel jaringan jantung diperoleh untuk pemeriksaan Angiotensin II type-1 reseptor (AT1-R). Selain itu, dilakukan analisis histopatologi pewarnaan Hematoxylin-Eosin dan Masson tricrome jaringan jantung, serta parameter stres oksidatif (NADPH oksidase, MDA dan SOD), serta gen yang mewakili inflamasi (NF-kB dan NLRP3). Hasil: DOXY menghambat peningkatan tekanan darah, cardiac index, LVPWd, dan IVSd. DOXY menurunkan parameter biomarker jantung (CK-MB dan LDH), ekspresi mRNA BNP dan TGF-β. Semua kelompok yang diobati dengan DOXY memperbaiki produksi stres oksidatif, sebagaimana dibuktikan dengan penurunan signifikan tingkat malondialdehid dan peningkatan aktivitas superoksida dismutase jaringan jantung. Perubahan ini sejalan dengan penurunan ekspresi mRNA dan ekspresi protein AT1R, p22phox, p47phox, NF-κB, dan NLRP-3. Pada pemeriksaan histopatologi, DOXY menghambat peningkatan cross sectional area dan myocardial fiber diameter. Kesimpulan: Secara keseluruhan, DOXY memiliki aktivitas penghambatan terjadinya cardiac remodeling pada tikus hipertensi kronik dengan uninefrektomi diikuti induksi DOCA dan garam fisiologis melalui jalur pensinyalan AT1 -R dan NADPH oksidase/ROS/NLRP-3 inflammasome.
Kata Kunci: Doksisiklin, hipertensi, stres oksidatif, inflammasome, DOCA.


Background: Hypertension encourages cardiac remodeling as a risk factor for heart failure preserved ejection fraction. Until now, therapy for heart failure triggered by chronic hypertension is based on clinical symptoms and cannot completely cure this condition. Doxycycline (DOXY) is a broad-spectrum antibiotic that has antioxidant activity. This study aimed to determine the protective effect of DOXY on cardiac remodeling in chronic hypertensive rats with uninephrectomy followed by induction of DOCA and physiological salt and the possible underlying mechanisms. Methods: Twenty-five male Sprague-Dawley rats were randomly divided into five groups: Normal, DOCA, DOCA+DOXY15, DOCA+DOXY30, and DOCA+Irbesartan. Normal group received normal saline orally. DOCA group underwent uninephrectomy and injected DOCA 20 mg/kgBW subcutaneously, 2x/week, and 1% NaCl in drinking water to induce chronic hypertension. While DOXY (15mg/kgBW and 30 mg/kgBW, respectively) and IRB (20mg/kgBW) orally, for five weeks. Blood pressure and echocardiography were checked. Blood serum was collected for cardiac biomarker examination. Heart tissue samples were obtained to examine AT1 -R. In addition, we analyzed the histopathological features of Hematoxylin-Eosin and Masson trichrome staining of heart tissue along with oxidative stress parameters (NADPH oxidase, MDA, and SOD), and genes representing inflammation (NF-kB and NLRP3). Results: DOXY inhibited increased blood pressure, cardiac index, LVPWd, and IVSd. DOXY decreased cardiac biomarker parameters (CK-MB and LDH), BNP, and TGF-β mRNA expression. All groups treated with DOXY improved oxidative stress production, as evidenced by a significant reduction in malondialdehyde levels and increased superoxide dismutase activity in cardiac tissue. These changes aligned with decreased mRNA expression and protein expression of AT1R, p22phox, p47phox, NF-κB, and NLRP-3. On histopathological examination, DOXY inhibited the increase in cross-sectional area and myocardial fiber diameter. Conclusion: Overall, DOXY inhibits cardiac remodeling in chronic hypertensive rats with uninephrectomy followed by DOCA and physiological salt induction through the AT1-R and NADPH oxidase/ROS/NLRP-3 inflammasome signaling pathways.
Keywords: Doxycycline, hypertension, oxidative stress, inflammasome, DOCA.