Klf15 Deficiency Is a Molecular Link Between Heart Failure and Aortic Aneurysm Formation

Abstract

Current therapies for diseases of heart muscle (cardiomyopathy) and aorta (aortopathy) include inhibitors of the renin-angiotensin system, β-adrenergic antagonists, and the statin class of cholesterol-lowering agents. These therapies have limited efficacy, as adverse cardiovascular events continue to occur with some frequency in patients taking these drugs. Although cardiomyopathy and aortopathy can coexist in a number of conditions (for example, Marfan's syndrome, acromegaly, pregnancy, and aging), pathogenetic molecular links between the two Copyright 2010 by the American Association for the Advancement of Science; all rights reserved. † To whom correspondence should be addressed. mukesh.jain2@case.edu. * These authors contributed equally to this work. SUPPLEMENTARY MATERIALwww.sciencetranslationalmedicine.org/cgi/content/full/2/26/26ra26/DC1 Fig. S1. Cardiovascular abnormalities in AngII-treated mice and cultured cells. Fig. S2. Baseline abnormalities in Klf15 −/− heart and aorta. Fig. S3. Cardiac mass and systolic blood pressure after AngII infusion. Fig. S4. Histologic parameters in aortas. Fig. S5. MMP-3 abundance in aortic smooth muscle. Fig. S6. p53 mRNA concentrations in heart and aortic tissue. Fig. S7. p300 abundance in hearts, curcumin administration protocol, and aortic morphometry after curcumin therapy. Table S1. Baseline cardiac parameters in Klf15 −/− and wild-type mice. Table S2. Cardiac parameters in Klf15 −/− and wild-type mice after AngII infusion. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript diseases remain poorly understood. We reasoned that identification of common molecular perturbations in these two tissues could point to therapies for both conditions. Here, we show that deficiency of the transcriptional regulator Kruppel-like factor 15 (Klf15) in mice leads to both heart failure and aortic aneurysm formation through a shared molecular mechanism. Klf15 concentrations are markedly reduced in failing human hearts and in human aortic aneurysm tissues. Mice deficient in Klf15 develop heart failure and aortic aneurysms in a p53-dependent and p300 acetyltransferase-dependent fashion. KLF15 activation inhibits p300-mediated acetylation of p53. Conversely, Klf15 deficiency leads to hyperacetylation of p53 in the heart and aorta, a finding that is recapitulated in human tissues. Finally, Klf15-deficient mice are rescued by p53 deletion or p300 inhibition. These findings highlight a molecular perturbation common to the pathobiology of heart failure and aortic aneurysm formation and suggest that manipulation of KLF15 function may be a productive approach to treat these morbid diseases.

Kruppel-like Factor 15 Is a Critical Regulator of Cardiac Lipid Metabolism

“…1C). Conversely, KLF15 has been shown to be substantially down-regulated in rodent models of heart failure (20,21), a pathologic state where myocardial lipid utilization is reduced (5,6). Consistent with this rodent data, we found KLF15 to be significantly reduced in failing human hearts with a significant recovery of expression after mechanical unloading with a left ventricular assist device (Fig.…”

“…Cell Culture-Neonatal rat ventricular myocytes (NRVM) were isolated from 2-day-old rat pups and isolated and maintained under standard conditions as described previously (20,21,27). Isolated NRVM were cultured for 24 -48 h under quiescent conditions by the inclusion of serum-free DMEM supplemented with insulin, transferrin, and selenium prior to experiments.…”

“…1D) (6). Although we have shown that KLF15 functions as a transcriptional repressor of prohypertrophic signaling in cardiomyocytes (20,21), the gene networks directly regulated by FIGURE 1. KLF15 is regulated in physiological and pathological conditions.…”

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

“…The delicate balance of the regulation of Lys382 acetylation for controlling p53 apoptotic activity was recently shown by the study of a new player in the field, namely, the zinc-finger transcription factor KLF15, which suppresses p53. It was shown that KLF15 inhibits the p300-dependent acetylation of Lys382 (Haldar et al, 2010), in contrast to the effect of HIPK2 that supports the acetylation. In KLF15 deficiency, p53 is highly acetylated and overactivated, leading to life-threatening condition of heart failure and aneurysm through a mechanism of p53-dependent muscle cells apoptosis.…”

“…In KLF15 deficiency, p53 is highly acetylated and overactivated, leading to life-threatening condition of heart failure and aneurysm through a mechanism of p53-dependent muscle cells apoptosis. KLF15-deficient mice can be rescued by p53 deletion or by p300 inhibition (Haldar et al, 2010). Thus, apoptosis that is considered mainly in the context of tumors should be avoided in normal cell biology to prevent dangerous physiological outcome in normal tissues.…”