Francesco Ramirez1, and Daniel B Rifkin2 – biography
1Mount Sinai School of Medicine
2NYU School of Medicine, New York
Recent studies have raised the intriguing possibility that losartan, the prototypical angiotensin II (AngII) receptor type 1 (AT1r) blocker (ARB), should be used as a prophylactic drug akin to aspirin and statins. Other reports however have questioned whether losartan is the real thing or is this a case of unbridled enthusiasm fueling yet another bubble. While only time will tell, it is worth reviewing the pros and cons regarding losartan’s broad therapeutic potential. Since FDA approval in 1995, ARBs have been widely used to treat hypertension, cardiac hypertrophy and renal disease owing to their selective antagonism of AngII-induced arterial muscle contraction, sympathetic pressor mechanisms and aldosterone release  Losartan was also shown to reduce AT1r-induced TGFβ activity in a mouse model of human cardiomyopathy . This last observation prompted investigators to test losartan in several experimental models of tissue fibrosis, as TGFβ is a potent determinant of extracellular matrix (ECM) deposition and remodeling. The studies eventually converged on the discovery that losartan also can mitigate thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS), a common connective tissue disease associated with mutations in the ECM protein fibrillin-1 . This seminal finding was welcomed by the medical community with understandable enthusiasm because it represented the first pharmacological treatment of a condition whose treatment options were thought to be restricted to gene or stem cell therapy.
Management of TAA progression in MFS currently relies on agents that lower blood pressure to delay aortic dilation and on elective aortic root replacement to prevent dissection and rupture. Aside from imparting structural properties to tissues, fibrillin-1 regulates cell performance by modulating extracellular bioavailability of latent TGFβ complexes. Consistent with the latter function, affected tissues from MFS patients and MFS mice display promiscuous TGFβ signaling, conceivably as the result of improper regulation of TGFβ bioavailability. Thus the beneficial impact of losartan treatment on vessel dilation and tissue degeneration may reflect respectively the drug’s anti-hypertensive and anti-TGFβ signaling properties, which are both highly desirable outcomes in MFS patients. Not only did losartan normalize aortic dilation and aortic wall architecture in MFS mice (Fbn1C1039G/+ mice), but a retrospective study of a small cohort of severely affected MFS children revealed an appreciable benefit of using ARBs to slow aortic root growth (Habashi 2006; Brooke 2008). Additionally, losartan was reported to improve skeletal muscle abnormalities of MFS mice and mice with either Duchene muscular dystrophy (DMD) or age-related sarcopenia [4;5]. Furthermore the finding that losartan significantly reduces tumor growth of AT1r over-expressing ERBB2-negative breast cancer xenografts implied potential applications in cancer therapy . The finding that improper TGFβ signaling is central to several pathological conditions therefore supports the notion that losartan may have pharmacological benefits beyond those originally envisioned, which presumably reflect the multiple biological functions of AT1r signaling (1;7]. However there are data advocating an alternative view.
In contrast to full TAA rescue in Fbn1C1039G/+ mice, losartan treatment only delays aortic dissection and rupture in Fbn1mgR/mgR mice, which have a more substantial fibrillin-1 abnormality and are more seriously affected than Fbn1C1039G/+ mice (Baxter B.T., personal communication). Losartan’s ability to blunt maladaptive aortic tissue remodeling in MFS mice therefore appears to be inversely proportional to the severity of the ECM defect, which determines the extent of both tissue impairment and TGFβ dysregulation. It follows that different MFS patients may respond differently to ARB treatment depending on the nature of the FBN1 mutation and genetic modifiers of ECM composition and TGFβ and/or AT1r activity. Additional studies have questioned the broad applicability of losartan and other ARBs. First, the original finding that TGFβ antagonism improves multiple manifestations in MFS mice was later counterbalanced by losartan’s inability to normalize skeletal abnormalities in these mutant mice [3;4;8]. Second, Bish et al.  recently showed that losartan treatment of DMD mice improves cardiomyopathy but not skeletal muscle degeneration, as previously reported . With respect to losartan and cancer therapy, decreasing TGFb signaling might in principle ameliorate the fibrosis associated with some tumors but might also promote growth of early neoplasms, as TGFβ is a potent tumor suppressor.
In spite of controversial findings, the above studies have brought us closer to developing therapeutic strategies for MFS that are based on experimental evidence and mechanistic insights. Irrespective of being either a proximal or distal effector of TAA progression, TGFβ has proven to be a viable biological target in a genetic disease with few other therapeutic options. This in turn provides the justification and means to search for highly specific small molecule inhibitors that will circumvent potential problems of losartan treatment, such as optimal dosage, genetic variability in drug response, long-term side effects etc. Even if losartan is not the anticipated panacea for MFS and other diseases, there is still significant merit in using AT1r antagonism to dissect pathogenic mechanisms and identify more suitable biological targets. Last but not least, the studies of MFS pathogenesis have underscored the physiological importance of an understudied research topic, namely ECM-mediated control of growth factor bioavailability. It seems therefore reasonable to conclude that perhaps we should embrace rather than repudiate controversial and paradoxical findings for they are the dialectic engine that propels scientific progress.
- Burnier M, Wuerzner G. (2011) Pharmacokinetic evaluation of losartan. Expert Opin. Metab. Toxicol. 7:643-649.
- Lim DS, Lutucuta S, Bachireddy P, Youker K, Evans A, Roberts R, Marian AJ. (2001) Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation 103:789-791.
- Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. (2008) Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl. J. Med. 358:2787-2795.
- Cohn RD, van Erp C, Habashi JP, Soleimani AA, Klein EC, Lisi MT, Gamradt M, ap Rhys CM, Holm TM, Loeys BL, Ramirez F, Judge DP, Ward CW, Dietz HC. (2007) Angiotensin II type 1 receptor blocade attenuates TGF--induced failure of muscle regeneration in multiple myopathic states. Nat. Med. 13:204-210.
- Burks TN, Andres-Mateos E, Marx R, Mejias R, Van Erp C, Simmers JL, Walston JD, Ward CW, Cohn RD. (2011) Losartan restores skeletal muscle remodeling and protects against disuse atrophy in sarcopenia. Sci. Transl Med.3:82ra37.
- Rhodes DR, Ateeq B, Cao Q, Tomlins S.A., Mehra R., Laxman B., Kalyana-Sundram S, Lonigro RJ, Helgeson BE, Bhojani MS, Rehemtulla A, Kleer CG, Hayes DF, Lucas PC, Varambally S, Chinnaiyan AM. (2009) AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist. Proc. Natl. Acad. Sci. 106:10284-10289.
- Mederos y Schnitzler M, Storch U, Gudermann T. (2011) AT1 receptors as mechanosensors. Curr. Opin. Pharmacol. 11:112-116.
- Nistala H, Lee-Arteaga S, Carta L, Cook JR, Smaldone S, Siciliano G, Rifkin AN, Dietz HC, Rifkin DB, Ramirez F. (2010) Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome. Hum. Mol. Genet. 19:4790-4798.
- Bish LT, Yarchoan M, Sleeper MM, Gazzara JA, Morine KJ, Acosta P, Barton ER, Sweeney HL (2011) Chronic losartan administration reduces mortality and preserves cardiac but not skeletal muscle function in dystrophic mice. PLoS One 6:e20856.
Current Comments contain the personal views of the authors who, as experts, reflect on the direction of future research in their field.
Posted in Pharmacology