The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus

Cardiovascular Diabetology

Tamás Radovits³  Béla Merkely²  Gábor Szabó³  Eszter Mária Horváth¹  Gábor Kökény⁴  Sevil Korkmaz-Icöz³  Mihály Ruppert²  Dalma Kellermayer²  Ede Birtalan²  László Hidi²  Attila Oláh²  Balázs Tamás Németh²  Csaba Mátyás² 

[1] Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Tűzoltó u. 37-47., Budapest, 1094, Hungary;Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest 1122, Hungary;Experimental Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, INF 326. OG 2, Heidelberg, 69120, Germany;Institute of Pathophysiology, Semmelweis University, Nagyvárad tér 4., Budapest, 1089, Hungary

关键词: Fibrosis;    Apoptosis;    PDE-5;    Oxidative stress;    Insulin dependent diabetes mellitus;    Diabetic complications;    sGC activator;    Pressure–volume relationship;    cGMP;    Heart failure;   

Others  :  1231866
DOI  :  10.1186/s12933-015-0309-x

 received in 2015-07-31, accepted in 2015-10-24,  发布年份 2015

【 摘 要 】

Background

Diabetes mellitus (DM) leads to the development of diabetic cardiomyopathy, which is associated with altered nitric oxide (NO)—soluble guanylate cyclase (sGC)—cyclic guanosine monophosphate (cGMP) signalling. Cardioprotective effects of elevated intracellular cGMP-levels have been described in different heart diseases. In the current study we aimed at investigating the effects of pharmacological activation of sGC in diabetic cardiomyopathy.

Methods

Type-1 DM was induced in rats by streptozotocin. Animals were treated either with the sGC activator cinaciguat (10 mg/kg/day) or with placebo orally for 8 weeks. Left ventricular (LV) pressure–volume (P–V) analysis was used to assess cardiac performance. Additionally, gene expression (qRT-PCR) and protein expression analysis (western blot) were performed. Cardiac structure, markers of fibrotic remodelling and DNA damage were examined by histology, immunohistochemistry and TUNEL assay, respectively.

Results

DM was associated with deteriorated cGMP signalling in the myocardium (elevated phosphodiesterase-5 expression, lower cGMP-level and impaired PKG activity). Cardiomyocyte hypertrophy, fibrotic remodelling and DNA fragmentation were present in DM that was associated with impaired LV contractility (preload recruitable stroke work (PRSW): 49.5 ± 3.3 vs. 83.0 ± 5.5 mmHg, P < 0.05) and diastolic function (time constant of LV pressure decay (Tau): 17.3 ± 0.8 vs. 10.3 ± 0.3 ms, P < 0.05). Cinaciguat treatment effectively prevented DM related molecular, histological alterations and significantly improved systolic (PRSW: 66.8 ± 3.6 mmHg) and diastolic (Tau: 14.9 ± 0.6 ms) function.

Conclusions

Cinaciguat prevented structural, molecular alterations and improved cardiac performance of the diabetic heart. Pharmacological activation of sGC might represent a new therapy approach for diabetic cardiomyopathy.

【 授权许可】

   
2015 Mátyás et al.

【 图 表 】

Fig.1.

Fig.2.

Fig.3.

Fig.4.

Fig.5.

Fig.6.

【 参考文献 】

• [1]Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther. 2014; 142:375-415.
• [2]Radovits T, Korkmaz S, Loganathan S et al.. Comparative investigation of the left ventricular pressure-volume relationship in rat models of type 1 and type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol. 2009; 297:H125-H133.
• [3]Radovits T, Bomicke T, Kokeny G et al.. The phosphodiesterase-5 inhibitor vardenafil improves cardiovascular dysfunction in experimental diabetes mellitus. Br J Pharmacol. 2009; 156:909-919.
• [4]Poirier P, Bogaty P, Garneau C, Marois L, Dumesnil JG. Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care. 2001; 24:5-10.
• [5]Joffe II, Travers KE, Perreault-Micale CL et al.. Abnormal cardiac function in the streptozotocin-induced non-insulin-dependent diabetic rat: noninvasive assessment with doppler echocardiography and contribution of the nitric oxide pathway. J Am Coll Cardiol. 1999; 34:2111-2119.
• [6]Sharma V, McNeill JH. Diabetic cardiomyopathy: where are we 40 years later? Can J Cardiol. 2006; 22:305-308.
• [7]Mourmoura E, Vial G, Laillet B et al.. Preserved endothelium-dependent dilatation of the coronary microvasculature at the early phase of diabetes mellitus despite the increased oxidative stress and depressed cardiac mechanical function ex vivo. Cardiovasc Diabetol. 2013; 12:49. BioMed Central Full Text
• [8]Pearson JT, Jenkins MJ, Edgley AJ et al.. Acute Rho-kinase inhibition improves coronary dysfunction in vivo, in the early diabetic microcirculation. Cardiovasc Diabetol. 2013; 12:111. BioMed Central Full Text
• [9]Cai L. Suppression of nitrative damage by metallothionein in diabetic heart contributes to the prevention of cardiomyopathy. Free Radic Biol Med. 2006; 41:851-861.
• [10]Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991; 43:109-142.
• [11]Radovits T, Arif R, Bomicke T et al.. Vascular dysfunction induced by hypochlorite is improved by the selective phosphodiesterase-5-inhibitor vardenafil. Eur J Pharmacol. 2013; 710:110-119.
• [12]Szabo G, Radovits T, Veres G et al.. Vardenafil protects against myocardial and endothelial injuries after cardiopulmonary bypass. Eur J Cardiothorac Surg. 2009; 36:657-664.
• [13]Hirschberg K, Radovits T, Loganathan S et al.. Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy. J Thorac Cardiovasc Surg. 2009; 137:1508-1514.
• [14]Loganathan S, Radovits T, Hirschberg K et al.. Effects of selective phosphodiesterase-5-inhibition on myocardial contractility and reperfusion injury after heart transplantation. Transplantation. 2008; 86:1414-1418.
• [15]Kukreja RC, Salloum FN, Das A. Cyclic guanosine monophosphate signaling and phosphodiesterase-5 inhibitors in cardioprotection. J Am Coll Cardiol. 2012; 59:1921-1927.
• [16]Schafer A, Fraccarollo D, Pfortsch S et al.. Improvement of vascular function by acute and chronic treatment with the PDE-5 inhibitor sildenafil in experimental diabetes mellitus. Br J Pharmacol. 2008; 153:886-893.
• [17]Stasch JP, Schmidt PM, Nedvetsky PI et al.. Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels. J Clin Invest. 2006; 116:2552-2561.
• [18]Korkmaz S, Radovits T, Barnucz E et al.. Pharmacological activation of soluble guanylate cyclase protects the heart against ischemic injury. Circulation. 2009; 120:677-686.
• [19]Radovits T, Korkmaz S, Miesel-Groschel C et al.. Pre-conditioning with the soluble guanylate cyclase activator Cinaciguat reduces ischaemia-reperfusion injury after cardiopulmonary bypass. Eur J Cardiothorac Surg. 2011; 39:248-255.
• [20]Salloum FN, Das A, Samidurai A et al.. Cinaciguat, a novel activator of soluble guanylate cyclase, protects against ischemia/reperfusion injury: role of hydrogen sulfide. Am J Physiol Heart Circ Physiol. 2012; 302:H1347-H1354.
• [21]Korkmaz S, Loganathan S, Mikles B et al.. Nitric oxide- and heme-independent activation of soluble guanylate cyclase attenuates peroxynitrite-induced endothelial dysfunction in rat aorta. J Cardiovasc Pharmacol Ther. 2013; 18:70-77.
• [22]Hirschberg K, Tarcea V, Pali S et al.. Cinaciguat prevents neointima formation after arterial injury by decreasing vascular smooth muscle cell migration and proliferation. Int J Cardiol. 2013; 167:470-477.
• [23]Irvine JC, Ganthavee V, Love JE et al.. The soluble guanylyl cyclase activator bay 58-2667 selectively limits cardiomyocyte hypertrophy. PLoS One. 2012; 7:e44481.
• [24]Frey R, Muck W, Unger S, Artmeier-Brandt U, Weimann G, Wensing G. Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers. J Clin Pharmacol. 2008; 48:1400-1410.
• [25]Lapp H, Mitrovic V, Franz N et al.. Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure. Circulation. 2009; 119:2781-2788.
• [26]Erdmann E, Semigran MJ, Nieminen MS et al.. Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure. Eur Heart J. 2013; 34:57-67.
• [27]Levy PD, Laribi S, Mebazaa A. Vasodilators in acute heart failure: review of the latest studies. Curr Emerg Hosp Med Rep. 2014; 2:126-132.
• [28]Gheorghiade M, Greene SJ, Filippatos G et al.. Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes. Eur J Heart Fail. 2012; 14:1056-1066.
• [29]Pacher P, Nagayama T, Mukhopadhyay P, Batkai S, Kass DA. Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats. Nat Protoc. 2008; 3:1422-1434.
• [30]Radovits T, Olah A, Lux A et al.. Rat model of exercise-induced cardiac hypertrophy: hemodynamic characterization using left ventricular pressure-volume analysis. Am J Physiol Heart Circ Physiol. 2013; 305:H124-H134.
• [31]Litwin SE, Raya TE, Anderson PG, Daugherty S, Goldman S. Abnormal cardiac function in the streptozotocin-diabetic rat. Changes in active and passive properties of the left ventricle. J Clin Invest. 1990; 86:481-488.
• [32]Snoeckx LH, Cornelussen RN, Van Nieuwenhoven FA, Reneman RS, Van Der Vusse GJ. Heat shock proteins and cardiovascular pathophysiology. Physiol Rev. 2001; 81:1461-1497.
• [33]Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87:315-424.
• [34]Lukowski R, Krieg T, Rybalkin SD, Beavo J, Hofmann F. Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond. Trends Pharmacol Sci. 2014; 35:404-413.
• [35]Fang L, Radovits T, Szabo G, Mozes MM, Rosivall L, Kokeny G. Selective phosphodiesterase-5 (PDE-5) inhibitor vardenafil ameliorates renal damage in type 1 diabetic rats by restoring cyclic 3′,5′ guanosine monophosphate (cGMP) level in podocytes. Nephrol Dial Transplant. 2013; 28:1751-1761.
• [36]Hamet P, Pang SC, Tremblay J. Atrial natriuretic factor-induced egression of cyclic guanosine 3′:5′-monophosphate in cultured vascular smooth muscle and endothelial cells. J Biol Chem. 1989; 264:12364-12369.
• [37]Koka S, Das A, Salloum FN, Kukreja RC. Phosphodiesterase-5 inhibitor tadalafil attenuates oxidative stress and protects against myocardial ischemia/reperfusion injury in type 2 diabetic mice. Free Radic Biol Med. 2013; 60:80-88.
• [38]Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 2014; 57:660-671.
• [39]Van Linthout S, Seeland U, Riad A et al.. Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol. 2008; 103:319-327.
• [40]Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 2002; 51:1938-1948.
• [41]Beyer C, Zenzmaier C, Palumbo-Zerr K, et al. Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFbeta signalling. Ann Rheum Dis. 2014. doi: 10.1136/annrheumdis-2013-204508 (Published ahead of print 23 February 2014).
• [42]Wang S, Mitu GM, Hirschberg R. Osmotic polyuria: an overlooked mechanism in diabetic nephropathy. Nephrol Dial Transplant. 2008; 23:2167-2172.