Declaration of conflict of interest

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1 Declaration of conflict of interest There is no any potential conflict of interest. There is not any financial commitments or funds from private companies.

2 Roles of heat shock transcription factor 1 gene (Hsf1) expressions in cardiac remodeling in a mouse model of senile cardiac amyloidosis Masamichi Hirose a, Jinze Qian b, Hisashi Shimojo b, Toshihide Kashihara b, Minoru Hongo c, Mituhiko Yamada b, Keiichi Higuchi b a) Iwate Medical University School of Pharmaceutical Sciences, Japan b) Shinshu University Graduate School of Medicine, Japan c) Shinshu University School of Health Sciences, Japan

3 Introduction I In mouse senile amyloidosis, misfolded serum apolipoprotein A-II (apoa-ii) deposits extracellularly in the whole body especially heart and is associated with aging. Heat shock transcription factor 1 (HSF1) are known to induce a set of heat shock proteins (Hsps) that can significantly suppress aggregate formation and cell death in many neurodegenerative disorders associated with the appearance of intracellular misfolded protein.

4 Introduction II Therefore, HSF1-induced Hsps expression may prevent amyloid depositions in cardiac tissues, leading to restoration of cardiac remodeling. However, whether these proteins can prevent cardiac remodeling induced in mouse senile cardiac amyloidosis is unknown.

5 Objective To examine roles of HSF1 gene expressions in the electrical and structural remodeling in a mouse model of senile cardiac amyloidosis.

6 Induction of mouse senile cardiac amyloidosis by fibril treatment Hsf1 -/- Apoa2 c ( ) 8 weeks of age amyloid fibril injection (1 mg) 16 weeks after Amyloidosis Hsf1 +/+ Apoa2 c () fibril

7 Amyloid index The degree and location of cardiac amyloid deposition in and mice with -treatment ** HSF1 KO Heart **p < 0.01 KO Others 16 weeks later Congo red (Anti-apoA-II)

8 Protein expression of HSF1 and Hsps in and mouse hearts with/without -treatment treatment + HSF1 Hsp27 Hsp40 Hsp70 *p < 0.05 **p < *** * * *** N.D. N.D. N.D. N.D. N.D. N.D HSF1 KO KO KO KO KO KO treatment

9 Methods Systemic blood pressure measurement Electrocardiogram (ECG) recording ECG lead II Echocardiography M-mode tracing Histological analysis Stained with masson s trichrome

10 Systemic blood pressure and heart rate of and mice with/without -treatment Group (n=7) treatment SBP DBP MBP HR (mmhg) (mmhg) (mmhg) (beats/min) 99±2.6 63±2.5 75± ±7 $ $ + 98±3.8 58±1.5 71± ±25 108±3.6 70±4.1 83± ± ±2.0 63±1.1 76± ±13 p>0.05, $ p<0.05 vs. non-treated mouse. p>0.05, &&& p<0.001 vs. non-treated mouse. SBP, systolic blood pressure; DBP, diastolic BP, MBP, mean BP; HR, heart rate &&&

11 Electrocardiographic parameters of and mice with/without -treatment Group (n=7) treatment P PR QRS QTc (ms) (ms) (ms) (ms) 19±0.5 42±0.6 19±0.7 31±1.5 && + 23±0.8 53±1.1 18±0.5 31±1.2 19±0.5 41±2.0 19±0.9 27±0.7 &&& + 21±1.0 43±1.5 18±0.3 28±1.5 p>0.05 vs. non-treated mouse. &&& p<0.001 vs. non-treated mouse.

12 Representative M-mode echocardiogram recorded from and mouse hearts Group treatment 1 cm s

13 Echocardiographic parameters in and mice with/without -treatment Group (n=7) treatment IVS LVEDd LVFS (mm) (mm) (%) 0.73± ± ±2.0 && ± ± ± ± ± ±0.9 &&& ± ± ±1.0 p>0.05 vs. non-treated mouse. & p<0.05, && p<0.01, &&& p<0.001, vs. non-treated mouse. &

14 Diameter (mm) Group The size of ventricular muscle cells treatment X HSF1 treatment KO KO

15 Conclusion Absence of HSF1 induces severe extracellular cardiac amyloid deposition and results in cardiac remodeling and dysfunction. HSF1 is a potential pharmacological approach in amyloidosis, and may be viewed as a novel therapeutic strategy for a variety of cardiac amyloidosis.